HUT69705A - Indole derivatives - Google Patents

Abstract

PCT No. PCT/US92/08306 Sec. 371 Date May 20, 1994 Sec. 102(e) Date May 20, 1994 PCT Filed Oct. 6, 1992 PCT Pub. No. WO93/11106 PCT Pub. Date Jun. 10, 1993Compounds of the formula <IMAGE> I wherein Z is <IMAGE> or <IMAGE> R1 is <IMAGE> re each independently C, N, O, or S; wherein the remaining variables are defined in the specification, and the pharmaceutically acceptable salts thereof. These compounds are useful psychotherapeutics and are potent serotonin (5-HT1) agonists and may be used in the treatment of depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, chronic paroxysmal hemicrania and headache associated with vascular disorders, and other disorders arising from deficient serotonergic neurotransmission. The compounds can also be used as centrally acting antihypertensives and vasodilators.

Description

The present invention relates to indole derivatives, processes for their preparation, intermediates for their preparation, and pharmaceutical compositions containing the indole derivatives according to the invention. The active compounds of the invention are useful in the treatment of migraine and other disorders.

U.S. Pat. No. 4,839,377 and European Patent No. 4,855,314 relate to 5-substituted 3-aminoalkylindoles. These compounds are considered useful for the treatment of migraine.

British Patent Application No. 040279 relates to 3-aminoalkyl-1H-indole-5-thioamides and carboxamides. These compounds are considered suitable for the treatment of hypertension, Raynaud's disease and migraine.

European Patent Application Publication No. 303,506

Refers to 3-polyhydropyridyl-5-substituted-1H-indoles. These compounds are considered to have potent 5 ag receptor agonist and vasoconstrictor activity and to treat migraine.

European Patent Application Publication No. 354,777 relates to N-piperidinyl-indolyl-ethyl-alkanesulfonamide derivatives. These compounds are considered to be 5HT1 receptor agonist and vasoconstrictor and useful in the treatment of headache.

The present invention relates to compounds of formula (I)

Z is a group of formula (I) or (2),

R 1 is a group of formula (3), (4), (5) or (6); X is -O-,> NH or -S-;

«·

A, B, D, E and F are each independently carbon, nitrogen, oxygen or sulfur;

R ₂ , R 3, R 4, R 5 and R 8 are each independently hydrogen, C 1-6 alkyl, aryl, (C 1-3 alkyl) aryl, halogen (e.g. fluoro, chloro, bromo or iodo) a cyano or nitro group, -NRyRg, ^- (CH2) m R9 / -SRg, -SO2R9, -SO2NR7R3, -NR7SO2R8, -NR7CO2R9, -NR7COR9, -CONR7R8 or -CO2R9; R 2 and R 3, R 3 and R 4, R ₄ and R 5 or R 5 and R 9 together are a 5-7 membered alkyl ring, a six membered aryl ring, a 5-7 membered heteroalkyl ring containing a nitrogen, oxygen or sulfur heteroatom or a 5 or 6 membered ring. a heteroaryl ring containing one or two heteroatoms selected from nitrogen, oxygen and / or sulfur;

R 7 and R 8 each independently represent hydrogen, C 1-6 alkyl, - (CH 2) q R 10, (C 1-3 alkyl) aryl, aryl, or R 7 and R ₈ together may form a 4- to 6-membered ring;

Rg is hydrogen, C1-6 alkyl, (C1-3 alkyl) aryl, aryl, or - (CH _{2) w} R h group;

And RIQ Rji is independently -OR 12 / ^- 12 ° C, 2 ^R / -CONHR12 radical or hydroxy and cyano;

^r12 is hydrogen, (C1-C6) -alkyl, aryl or (C1-C6-alkyl) -aryl;

R 13 is hydrogen, -O R _14, or -NHCOR ₁₄ ;

R 14 is C 1-6 alkyl or (C 1-3 alkyl) aryl;

n is 0 1 obsession 2; m is 1 2 obsession 3; q is 2, 3 obsession 4; w is 2, 3 obsession 4; and

the aryl moieties of the above aryl groups and alkylaryl groups are independently phenyl or substituted phenyl, wherein the substituent is one to three C 1-4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro and C 1-4 alkoxy groups. may;

and the dotted line represents an optional double bond;

and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment of migraine and other conditions described below.

The compounds of the present invention include all optical isomers of the compound of formula (I) (e. G., The R and S enantiomers) as well as racemic and diastereomeric mixtures thereof. When R 1 is a group of Formula 6, it is preferred that the compound is R diastereomeric with respect to the chiral carbon atom *. When R13 is -OR14 or -NHCOR14, cis epimers [(2R, 4R) absolute configuration] are particularly preferred.

Unless otherwise indicated, alkyl groups and alkyl moieties occurring in other groups (e.g., alkoxy) may be linear or branched, and may be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and may be linear or branched, and may contain ring units.

Preference is given to compounds of formula (I) according to the invention wherein R 1 is a group of formula (3), (4) or (6a), wherein R 7, R 8 and R 13 are as defined above;

Z is a group of formula (Ia) or (2a) wherein A, D, E, R 2, R 3, R 4 and R 5 are as defined above; X is> NH.

The compounds of the invention described above include compounds of formulas (7), (8) and (9).

The following compounds are particularly preferred:

3- (2-dimethylamino-ethyl) -5- (3,5-dinitro-pyrid-2-ylamino) -1H-indole;

3- (2-dimethylamino-ethyl) -5- (3-nitro-pyridin-2-ylamino) -ΙΗ-indole;

3- (2-dimethylamino-ethyl) -5- (3-trifluoromethyl-pyridin-2-ylamino) -ΙΗ-indole;

(R) -5- (3-nitro-pyrid-2-ylamino) -3- (pyrrolidin-2-ylmethyl) -1H-indole;

(R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (nitro-pyrid-2-ylamino) -1H-indole;

(R, S) -3- (N-Methyl-pyrrolidin-3-yl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole;

5- (benzoxazine-2-ylamino) -3- (2-dimethylamino-ethyl) -ΙΗ-indole;

(R) -3- (N-Cyclopropylmethyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -5-indole;

(R) -5- (3-Nitro-pyrid-2-ylamino) -3- [N- (2-propynyl) -pyrrolidin-2-ylmethyl] -1H-indole;

(R) -5- (3-nitro-pyrid-2-ylamino) -3- (N- (2-propenyl) -pyrrolidin-2-ylmethyl) -5-indole;

(R) -5- (3-Nitro-pyrid-2-ylamino) -3- (N-propyl-pyrrolidin-2-ylmethyl) -1H-indole;

(R) -3- (N-Butyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -5-indole;

(R) -3- (N-Ethyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole;

(R) -5- (3-Nitropyrid-2-ylamino) -3- (N-pentylpyrrolidin-2-ylmethyl) -5-indole;

(R) -3- [N- (2-Methoxy-ethyl) -pyrrolidin-2-ylmethyl] -5- (3-nitro-pyrid-2-ylamino) -1H-indole;

5- (4-Benzyl-1,3-thiaz-2-ylamino) -3- (2-dimethylaminoethyl) -1H-indole;

(R) -5- (3-Benzylthio-1,2,4-thiadiaz-5-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole;

3- (2-Dimethylaminoethyl) -5- (pyrimidin-2-ylamino) -5-indole;

3- (2-Dimethylaminoethyl) -5- (3-methylsulfonylpyrid-2-ylamino) -indole;

(R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (2-nitrophenylamino) -1H-indole;

(R) -5- (6-Methoxy-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole;

(R) -5- (4-Methyl-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole;

(R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-5-phenyl-pyrid-2-ylamino) -1H-indole;

(R) -5- (3-Cyanopyrid-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole;

(R) -5- (6-Isopropoxy-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole;

(R) -5- (4-cyano-2-nitro-phenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -lH-indole;

(R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (4-trifluoromethyl-2-nitrophenylamino) -1H-indole;

(R) -5- (5,6-Dichloro-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole;

5- (4-Cyano-2-nitro-phenylamino) -3 - [(2R, 4R) -N-methyl-4-methoxy-pyrrolidin-2-ylmethyl] -1H-indole;

(R) -5- (5-Chloro-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole;

(R) -3- [N- (2-Cyanoethyl) pyrrolidin-2-ylmethyl] -5- (3-nitropyrid-2-ylamino) -1H-indole; and (R) -3- [N- (2-cyanomethyl) pyrrolidin-2-ylmethyl] -5- (3-nitropyrid-2-ylamino) -1H-indole.

Other specific compounds of the invention include:

6- [3- (2-Dimethylaminoethyl) -indol-5-ylamino] -purine;

3- (2-dimethylamino-ethyl) -5- (2-nitro-phenylamino) -lH-indole;

3- (2-dimethylamino-ethyl) -5- (3-aminocarbonyl-pyrid-2-ylamino) -lH-indole;

3- (2-dimethylamino-ethyl) -5- (2,6-dinitro-phenylamino) -lH-indole;

3- (2-dimethylamino-ethyl) -5- (2-cyano-phenylamino) -lH-indole;

3- (2-dimethylamino-ethyl) -5- (2,4-dinitro-phenylamino) -lH-indole;

3- (2-dimethylamino-ethyl) -5- (6-ethoxycarbonyl-3-methylthio-1,2,4-triazin-5-ylamino) -lH-indole;

5- (1-phenyl-tetrazol-5-yl-amino) - (2-dimethylamino-ethyl) -lH-indole;

5- (3-nitropyrid-2-yl-amino) -3- (piperidin-4-yl) -1H-indole;

5- (3-nitro-pyridin-2-ylamino) -3- (1,2,5,6-tetrahydropyrid-4-yl) -ΙΗ-indole;

5- (5-nitro-pyridin-2-ylamino) -3- (1,2,5,6-tetrahydropyrid-4-yl) -ΙΗ-indole;

5- (3-nitro-pyridin-2-yloxy) -3- (1,2,5,6-tetrahydropyrid-4-yl) -1H-indole;

5- (5-nitro-pyrid-2-yloxy) -3- (1,2,5,6-tetrahydro-pyrid-4-yl) -1H-indole;

3- (2-dimethylamino-ethyl) -5- (3-amino-pyrid-2-ylamino) -lH-indole;

3- (2-dimethylamino-ethyl) -5- (3-phenyl-amino-pyrid-2-ylamino) -ΙΗ-indole;

3- (2-dimethylamino-ethyl) -5- (6-benzyl-aminocarbonyl-3-methylthio-1,2,4-triazin-5-ylamino) -lH-indole;

5-Amino-3- (N-methylpyrrolidin-3-yl) -lH-indole;

(R) -5-amino-3- (N-methylpyrrolidin-2-ylmethyl) -ΙΗ-indole;

(R) -5-Amino-3- (pyrrolidin-2-ylmethyl) -α-indole.

This invention relates to hypertension, depression, anxiety, eating disorders, obesity, drug addiction, headache, migraine, pain, chronic, one-sided headaches and vascular headache-related pharmaceutical compositions effective to treat such conditions. They comprise a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

For treating hypertension, depression, anxiety, eating disorders, obesity, drug addiction, headaches, migraine, pain, chronic unilateral headaches and seizures associated with vascular disorders, a mammal (e.g. an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of such conditions.

The compounds or compositions of the present invention are also useful in the treatment of disorders resulting from serotonergic neurotransmission which is defective (e.g., depression, anxiety, eating disorders, obesity, drug addiction, headache, migraine, pain, chronic, unilateral headache and vascular), a method of treatment comprising administering to a mammal (such as a human) in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to compounds of formula (II) wherein X and R ₃ are as defined for formula (I). The compounds of formula (II) may be used, for example, as intermediates in the preparation of compounds of formula (I).

The invention will now be described in more detail.

Compounds of formula (I) are prepared as shown in Scheme 1 by reacting a starting compound of formula (II) wherein R1 and X are as defined for formula (I) with a reagent of formula (IIIA) or (IIIB). wherein A, B, D, E, F, R ₂₁ ^R 3 R 4 R 4 R 5 R 5 are Rg are as defined above for formula (I) and LG is a leaving group such as Cl, Br, I, -SCH ₃ , -SO ₂ CH ₃ , -SPh or -SO ₂ Ph (Ph = phenyl). This

the reaction may be carried out under acidic, basic or neutral conditions, generally at elevated temperatures. Suitable bases include sodium bicarbonate, trialkylamines, sodium hydride and sodium carbonate. Among the bases, triethylamine is preferred. Suitable acids include mineral acids (e.g., hydrochloric and hydrobromic) and organic acids (e.g., acetic acid). Acetic acid is preferred. Suitable solvents include methanol, ethanol, dioxane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide. Ethanol is the preferred solvent. The reaction is usually carried out at a temperature of from about 50 ° C to about 154 ° C, preferably from about 70 ° C to about 80 ° C.

Compounds of formula II may be prepared as shown in Scheme 2.

Compounds of formula (VI) wherein R g is a protected heteroatom containing moiety, such as -N (Ris) 2 '-NHRis / ^-or 18 / ^sr 18, 2,5-dimethyl-1H-pyrrole. or -NO ₂ and R 18 is hydrogen, benzoyl or benzyl - a compound of formula VII wherein R 15 is -SH, -NH ₂ or -OH with benzyl or benzoyl halide (preferably benzyl bromide or benzoyl chloride) or by reaction with acetylacetone in the presence of a base in an inert solvent in a manner known to those skilled in the art. The corresponding compounds of formula (VII) are commercially available or may be prepared by methods known to those skilled in the art. Suitable bases include sodium bicarbonate, sodium carbonate, sodium hydride and trialkylamines. A preferred base is triethylamine. THE • · · ·

Suitable solvents include dimethylformamide, ethers (including tetrahydrofuran), and C 1-3 alcohols. A preferred solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of about 25 ° C to about 100 ° C, preferably about 25 ° C.

Compounds of formula (V) may be prepared by reacting a compound of formula (VI), wherein R g is as previously defined for formula (IV), with a suitable electrophile under acidic, basic or neutral conditions. Suitable electrophiles include N-protected proline acid chlorides, N-protected 4-piperidones, oxalyl chloride and maleimides. When using oxalyl chloride, the resulting indole-3-glyoxamic acid chloride is further reacted with a secondary amine of formula NHRgRg wherein R5 and Rg are as defined for formula (I). Suitable acids include mineral acids, acetic acid and formic acid. Suitable bases include Grignard reagents, including ethyl magnesium bromide, primary and secondary or tertiary amines, sodium or potassium metal, or sodium hydride. Suitable solvents include ethers (including tetrahydrofuran and diethyl ether), benzene, toluene, acetic acid, formic acid, and C 1 -C 4 alcohols. The reaction is generally carried out at a temperature from about 0 ° C to about 150 ° C, preferably from about 0 ° C to about 120 ° C. In the case where N-protected proline acid chloride is used as the electrophile, benzene is the preferred solvent, the reaction is preferably carried out under alkaline conditions, preferably using ethyl magnesium bromide as the base, and the reaction is preferably 0 · · * · · · ········· ······ · · ·

- 12 ° C. In the case where N-protected 4-piperidone is used as the electrophile, methanol is the preferred solvent, preferably the reaction is carried out under alkaline conditions, preferably sodium methoxide, and preferably at about 65 ° C. In the case where oxalyl chloride is used as the electrophile, the ether is the preferred solvent, the reaction is preferably carried out under alkaline conditions, preferably with HNRgRg as the preferred base, and preferably at about 0 ° C. When maleimide is used as the electrophile, the preferred solvent is acetic acid, the reaction is preferably carried out under acidic conditions, preferably acetic acid, and preferably at about 101 ° C.

Compounds of formula (IV) may be prepared from compounds of formula (V) - wherein R17 is a group of formula (10), (11), (12) or (13), and R5 and Rg are as previously described in formula (I). R ^g is as defined above for Formula IV and Rj_9 is a tert-butyl group or a benzyl group by hydride reduction in an inert solvent. Suitable reducing agents include lithium aluminum hydride, lithium borohydride and diborane. Lithium aluminum hydride is preferred. Suitable solvents include tetrahydrofuran, dioxane and other ethers. A preferred solvent is tetrahydrofuran. The reaction is generally carried out at a temperature of about 25 ° C to about 100 ° C, preferably about 65 ° C.

Compounds of Formula II are Compounds of Formula IV ♦ ·· · ···· ·

They can be prepared from 13 compounds by deprotection of the heteroatom using a transition metal catalyst and a hydrogen source or hydroxylamine hemi (hydrochloride). Suitable solvents include C 1-4 alcohols, ethyl acetate, acetone and dimethylformamide. A preferred solvent is ethanol. Suitable transition metal catalysts include palladium on carbon, palladium on hydroxide and platinum oxide. A preferred catalyst is palladium hydroxide on carbon. Suitable sources of hydrogen include hydrogen gas, ammonium formate, and formic acid. Hydrogen gas is preferred, which is generally applied at a pressure of (9.8-29.4) · 10 ⁴ Pa, preferably 29.4 · 10 ⁴ Pa. The reaction is usually carried out at a temperature of about 25 to 100 ° C, preferably about 40 ° C.

Compounds of formula (VII) are commercially available.

The compounds of formula (II) may also be prepared by methods known to those skilled in the art, for example, as described in Shaw, E. and Woolley, D.W., J. Am. Chem. Soc. , 16, 17, 21 or 25. Compounds of formula (III) are also commercially available or may be prepared by methods known to those skilled in the art.

Compounds of formula (I) may also be prepared by alkylation of compounds of formula (IC) wherein Ζ, X and n are as defined above, by reaction with an alkylating agent and a base in an inert solvent. Suitable alkylating agents include alkyl halides

(chlorides, bromides or iodides), alkyl tosylates, alkyl mesylates, alkyl triflates, α, β-unsaturated ketones, α, β-unsaturated esters, α, β-unsaturated amides and, β-unsaturated nitriles are the desired R 7 depending on the group. Alkyl halides (iodides) are preferred. Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, dioxane, N, N-dimethylformamide, ethanol, propanol and methanol. A preferred solvent is acetonitrile. The reaction is generally carried out at a temperature of about 0 ° C to 150 ° C, preferably about 25 ° C to 65 ° C.

Unless otherwise indicated, the pressure used in the above reactions is not critical. The reaction is generally carried out in the range of atmospheric pressure to three times the atmospheric pressure, preferably at atmospheric pressure.

Compounds of general formula (I) of basic nature tend to form a wide variety of different salts with various inorganic and organic acids. Although they must be pharmaceutically acceptable for administration of such salts to an animal, it is often desirable in practice to isolate a compound of Formula (I) from the reaction mixture first in the form of a pharmaceutically unsuitable salt and then to readily reconstitute it with an alkaline reagent. and then converting the free base into a pharmaceutically acceptable acid addition salt. Conversion of the basic compounds of the invention to the acid addition salt can be readily accomplished by substantially equivalent amounts of the selected mineral or organic acid in an aqueous medium or in a suitable organic solvent such as methanol. or in ethanol. Carefully evaporation of the solvent affords the desired solid salt.

The acids which can be used to form the acid addition salts of the basic compounds of the invention are those which form non-toxic acid addition salts, i.e. salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydrogen iodide, nitrate, sulfate, hydrogen sulfate, phosphate , acetate, lactate, citrate, hydrogen phosphate, acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylenedis ( naphthoate).

Acidic compounds of formula I, such as those wherein Z contains a carboxylate moiety, tend to form basic salts with various pharmaceutically acceptable cations. Such salts include the alkali metal and alkaline earth metal salts, in particular the sodium and potassium salts. These salts may be prepared by conventional procedures. Bases which can be used as reagents for the preparation of pharmaceutically acceptable basic salts of the compounds of the invention include those which form non-toxic basic salts with the acidic compounds of formula (I) described above. These non-toxic basic salts include salts containing pharmaceutically acceptable cations such as sodium, potassium, calcium and magnesium. These salts can be readily prepared by reacting the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably in vacuo. Alternatively, these compounds may be prepared by mixing a solution of the acidic compound in a lower alkanol with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness as described above. In both cases, it is preferable to use the stoichiometric amounts of the reagents to complete the reaction and obtain the maximum yield of the desired product.

The compounds of formula (I) and their pharmaceutically acceptable salts (hereinafter referred to as active ingredients of the invention) are useful psychotherapeutic agents and potent serotonin (5-HTf) agonists, useful in depression, anxiety, eating disorders, obesity, drug dependence, headache, migraine, chronic unilateral headaches in seizures and headaches associated with vascular disorders, pain and other disorders resulting from defective serotonergic neurotransmission. The compounds may be used as centrally acting antihypertensive agents and vasodilators. The evaluation of the active compounds of the present invention as anti-migraine agents is carried out by determining their ability to mimic the effect of sumatripan in the constriction of an isolated canine saphenous vein strip [P.P.A. Humprey et al., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked by a known serotonin antagonist, methiotepin. Sumatriptan is known to be useful in the treatment of migraine and to induce selective growth in the anesthetized dog's carotid artery resistance. It is assumed that the effect ·······················································•

- 17 firmness is based on this effect [W. Fenwick et al., 1989, Br. J. Pharmacol., 96, 83].

The compositions of the invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active ingredient of the present invention may be formulated for oral, oral, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, and for inhalation or insufflation.

Pharmaceutical formulations for oral administration may be, for example, tablets or capsules prepared by conventional means for therapeutic use, such as excipients (e.g., pregelatinised corn starch, polyvinylpyrrolidone) or hydroxypropylmethylcellulose; fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrating agents (e.g., potato starch or sodium starch glycolate) or wetting agents (e.g., sodium lauryl sulfate). The tablets may also be coated by a known method. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may be formulated in conventional manner with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia ·· • «« «* _w · · · · * * * ·· ·· · · *" ·· "· 4" ·

- 18 gums); non-aqueous carriers (e.g. almond oil, oil esters or ethyl alcohol) and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

For oral administration, tablets or lozenges may be formulated in conventional manner.

The active compounds of the present invention may be formulated for parenteral administration by injection, including the use of conventional catheter procedures or infusions. Formulations for injection may be presented in unit dosage form, for example, in a ampoule or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active compounds may be formulated as powders which must be reconstituted with the appropriate vehicle, e.g., sterile, pyrogen-free water, before use.

The active compounds of the present invention may also be formulated into rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

For the preparation of compositions for intranasal administration or administration by inhalation, the active compounds of the present invention are preferably pressed or pumped from a pump spray container in the form of solutions or suspensions, and aerosol sprays using a pressurized container or aerosol preparation may be employed. ··· ** ···· · ** ·

19, using suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. For pressurized aerosol formulations, the dosage unit may be adjusted using a valve to deliver a metered amount. Pressurized containers or aerosol devices may contain a solution or suspension of the active compound. Formulations for inhalation or insufflation may be in the form of capsules or liners (e.g., made from gelatin) containing a powder mix of a compound of the invention and a suitable powder base (e.g., lactose or starch).

For oral, parenteral or oral administration of the active compound of the invention, the recommended dosage for the average adult human is to treat the conditions mentioned above (e.g., migraine) in the range of 0.1 to 200 mg of active ingredient per unit dose, for example 1 to 4 times. daily.

Aerosol formulations for the treatment of the aforementioned conditions (e.g. migraine) are preferably administered to an average adult human such that the aerosol administered dose or stroke contains from about 20 pg to about 1000 pg of the active ingredient. The average daily dose of aerosol is between 100 pg and 10 mg. Dosage may be several times daily, for example 2, 3, 4 or 8 times, for example once, for example 1, 2 or 3 doses.

The following examples illustrate the preparation of the compounds of the present invention, but are not intended to limit it. The melting points given are not corrected. NMR data ppm • ·

- 20 (5) and refer to the solvent deuterium lock signal. Specific rotations were measured at room temperature using the sodium D line (589 nm). Unless otherwise noted, all mass spectra were recorded under electron impact conditions (E1, 70 eV).

Commercial reagents were used without further purification. Chromatography refers to column chromatography using a silica gel packing of 32-63 μιη in the form carried out under nitrogen pressure (flash chromatography). At room temperature we mean 20-25 ° C.

Example 1

General procedure for the synthesis of 5-arylamino-1H-indoles by condensation of 5-aminoindole derivatives with halogenated aromatic hydrocarbons

A solution of 2.00 mmol of 5-aminoindole, 3.00 mmol, 1.5 equivalents of halogenated aromatic hydrocarbon and a base (3.00 mmol) in 10 mL of anhydrous solvent, depending on the substrate, under reflux under nitrogen atmosphere 1 Boil for -18 hours or stir at room temperature for 1 hour. The reaction mixture was cooled and chromatographed directly on silica gel (50 g) eluting with 9: 1: 0.1 methylene chloride: methanol: ammonium hydroxide. In some cases, the 5-arylamino-1H-indole derivative obtained after the chromatographic process is recrystallized to give an analytically pure sample.

Using the above procedure, the following compounds were prepared:

A. 3- (2-Dimethylaminoethyl) -5- (3-nitropyrid-2-ylamino) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) indole (Shaw, E. and Woolley, D.W., J. Am. Chem. Soc., 1957, 1877) and 2-chloro-3-

-nitropyridine is used. The base was triethylamine and the solvent was p-dioxane and the reaction was refluxed for 3 hours (101 ° C). Chromatography gave the title product as a dark red foam (67%). Melting point: 59.0-61.0 ° C.

³ H-NMR (CDCl ₃ ): δ = 8.66 (bs, 1H), 8.51 (dd, J = 8.3 and

1.8 Hz, 1H), 8.41 (dd, J = 4.4 and 1.8 Hz, 1H), 7.76 (broad s, 1H), 7.30-7.24 (m, 2H) , 6.97 (d, J = 2.1 Hz, 1H), 6.73 (dd, J =

8.3 and 4.4 Hz, 1H), 2.97-2.91 (m, 2H), 2.70-2.63 (m, 2H), 2.36 (s, 6H); ¹³ C NMR (CDCl 3): 155.7, 151.5, 135.5, 134.5, 129.4,

128.2, 127.9, 122.8, 119.3, 114.4, 114.3, 113.0, 111.5, 60.3,

45.4, 23.7.

Analysis calculated for C 17 H 19 N ₅ O ₂ · 1/3 · ₃ Ο: C, 61.62; H, 5.98; N, 21.13. Found: C, 61.58; H, 5.65; N, 20.80.

B. 3- (2-Dimethylaminoethyl) -5- (2-nitrophenylamino) -

indole

5-Amino-3- (2-dimethylaminoethyl) indole and 2-fluoronitrobenzene are used. Pyridine was used as base, bromobenzene as solvent and the reaction was heated to reflux (156 ° C) for 11 hours. Chromatography afforded the title compound as a dark red solid (82%). Mp 116.0-117.0 ° C; ¹³ C-NMR (CD 3 OD): δ 146.7, 136.7, 133.2, 131.0, 129.5, 127.2,

124.7, 121.3, 117.3, 117.2, 117.0, 114.1, 113.4, 61.4, 45.4,

24.2; HRMS calculated for C ₁₈ H ₂₀ N ₄ O ₂ 342.1588; found: 324.1564.

Analysis for the formula CxgH20 2'V ^N 4 ^{0 3} H ₂ 0: Calculated: C% = 65.44, H% = 6.31, N% = 16.96; Found: C, 65.44; H, 5.92; N, 16.62.

C. 3- (2-Dimethylaminoethyl) -5- (3,5-dinitropyrid-2-yl)

amino) indole

5-Amino-3- (2-dimethylaminoethyl) indole and 2-chloro-3,5-dinitropyridine are used. The base was triethylamine and the solvent was tetrahydrofuran and the reaction was carried out at room temperature for 1 hour. Direct filtration of the reaction mixture gave a red solid which was recrystallized from ethanol. The title compound was obtained in 7% yield as a red solid. Melting point: 194.0-195.0 ° C; ³³ C-NMR (DMSO-d 6): δ 152.2, 150.7, 134.7, 134.1, 131.2, 128.2, 127.1,

126.7, 123.9, 119.1, 114.8, 112.7, 111.4, 59.7, 44.9, 22.8;

HRMS calcd for C ₁₇ H ₁₈ N ₈ O ₄ : 370.1391; found: 370.1358.

Analysis calculated for C 17 H 18 N ₈ O 4 · 1 / 2H ₂ O: C, 53.82; H, 5.04; N, 22.15; Found: C, 53.55; H, 4.56; N, 21.98.

D. 3- (2-Dimethylaminoethyl) -5- (3-aminocarbonylpyrid-2-ylamino) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) indole and 2-chloronicotinamide are used. Pyridine was used as base, bromobenzene as solvent and the reaction was heated to reflux (156 ° C) for 18 hours. After chromatography, the resulting solid was recrystallized from methanol / water to give the title compound as a yellow solid (36%). 127.0129.0 ° C; ¹³ C-NMR (CD ₃ OD): δ 173.0, 157.9, 152.2, 139.0, 135.4,

132.4, 129.0, 123.9, 119.1, 113.7, 113.2, 113.0, 112.5, 111.3,

61.4, 45.4, 24.3; HRMS calcd for ^C 18 ^H 21 ^N 5 °:

323.1748; found: 323.1726.

Analysis calculated for CΟχΟχΙΙ ιι HΟΟ: C, 63.33; H, 6.79; N, 20.51. Found: C, 63.19; H, 6.50; N, 20.30.

E. 3- (2-Dimethylaminoethyl) -5- (2,6-dinitrophenylamino) -

indole

5-Amino-3- (2-dimethylaminoethyl) indole and 1-chloro-2,6-dinitrobenzene are used. The base is triethylamine and the solvent is tetrahydrofuran. The reaction was carried out at room temperature for 1 hour. Chromatography afforded the title compound as a dark red solid (57%). Melting point: 187.0-188.0 ° C. ¹³ C-NMR (DMSO-d 6) δ 139.9, 135.2, 134.0, 132.0, 131.8, 127.2, 123.8, 117.0,

115.4, 112.9, 112.0, 109.3, 59.9, 45.1, 23.0; HRMS calcd for ^C 18 ^H 19 ^N 5 O: 369.1439; found: 369.1428.

Analysis Ο 19 ^ 8 ^{Η Ν} 5 ° O: Calculated: C% = 58.53, H% = 5.18, N% = 18.96; Found: C, 58.45; H, 4.96; N, 18.63.

F. 3- (2-Dimethylaminoethyl) -5- (2-cyanophenylamino) -1H-

indole

5-Amino-3- (2-dimethylaminoethyl) indole and 2-fluorobenzonitrile are used. Pyridine was used as base, 2-fluorobenzonitrile as solvent, and the reaction was stirred at reflux for 8 hours. Chromatography afforded the title compound as a clear, light brown oil (2%). ³ H-NMR (CD ₃ OD) δ 7.43 (dd, J = 7.7 and 1.5 Hz,), 7.38 (d, J = 1.9 Hz, 1H), 7.34 (d , J = 8.6 Hz, 1H), 7.30-7.23 (m, 1H), 7.07 (s, 1H),

6.97 (dd, J = 8.6 and 1.9 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H),

6.73-6.67 (m, 1H), 4.91 (s, 2H), 2.92-2.86 (m, 2H), 2.65-2.59 (m, 2H), 2, 30 (s, 6H); HRMS calcd for CpgH2o ^N4 O: 304.1690; found: 304.1682.

G. 3- (2-Dimethylaminoethyl) -5- (3-trifluoromethylpyrid-2-ylamino) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) indole and 2-chloro-3-trifluoromethylpyridine are used. Pyridine was used as base, Ν, Ν-dimethylformamide as solvent and the reaction was refluxed at 153 ° C for 18 hours. Chromatography affords the title compound as a clear, light brown oil (10%). ¹³ C-NMR (CD 3 OD)? 5 155.4, 152.3, 136.9, 136.1, 131.7, 129.0, 124.0,

120.9, 115.7, 113.9, 113.5, 112.5, 110.5, 61.4, 45.4, 24.3;

LRMS (m / z, relative intensity) 348 (100, M ⁺ ), 303 (16), 290 (28), 268 (11), 250 (20); HRMS calcd for C ₁₈ H ₁₉ F ₃ N 4: 348.1564; found: 348.1532.

H. 3- (2-Dimethylaminoethyl) -5- (2,4-dinitrophenylamino) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) indole and 1-chloro-2,4-dinitrobenzene are used. As the base, triethylamine, solvent ♦ · · · · · ·

Sulfur was used in tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Chromatography afforded the title compound as a dark red solid (73%). Melting point: 177.0-179.0 ° C. ¹³ C-NMR (DMSO-d ₆ ) δ 148.2, 135.6, 135.2,

130.1, 129.6, 128.2, 127.9, 124.3, 123.5, 119.6, 116.9, 116.3,

113.3, 112.5, 60.0, 45.2, 23.0; FAB HRMS calcd for ^C 18 ^H 19 ^N 5 ° 4 * E ^{h +} ] 370.1517, found 370.1492.

I. (R) -5- (3-Nitro-pyrid-2-ylamino) -3- (pyrrolidin-2-yl)

-methyl) -1H-indole (R) -5-amino-3- (pyrrolidin-2-ylmethyl) -indole and 2-chloro-3-nitropyridine are used. Sodium acetate was used as base and acetic acid was used as solvent, and the reaction was heated to reflux (116 ° C) for 2 hours.

Column chromatography afforded the title compound as a dark red foam (% yield). 1 H-NMR (CDCl ₃ ): δ

J = 1.8 and

10.05 (brs, 1H), 9.23 (brs, 1H), 8.49 (dd,

θ 3 Hz, 1H), 8.39 (1.8 and 4.5 Hz, 1H), 7.70 (d, J = 1.7 Hz) 1H), 7.33-7.22 (M, 2 H) , 6.98 (s, 1H); 73 (dd, J = 4.5 and 8, Hz, 1H), 3.46- 3.34 (M, 1H), 3.10-2.97 (M, 1H), 2.97-2.78 (m 3H), 1.99 to 1.64 (M, 3H), 1.56-1.42 (m, 1H) ; ^13c NMR (CDCl3)

δ

151.5,

129.2,

155.7, f

f

135.5, 134.5,

128.1, 127.8, 123.8, 119.4,

114.3,

113.0,

111.6, 59.5,

45.7,

31.3, 30.6, 24.7; FAB LRMS (m / z, relative intensity):

338 (6, (100)).

Analysis CI8 ^H i9 ^N ° 5 * ⁰ 2 ^{67 C} 2 ^H 4 O 2 [acetic acid] wherein:

• · · «• · ·

Calculated: C, 61.53; H, 5.79; N, 18.56.

Found: C, 61.57; H, 5.74; N, 18.82.

J. (R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole (R) -3- (N- methylpyrrolidin-2-ylmethyl) indole and 2-chloro-3-nitropyridine are used. The base is triethylamine and the solvent is acetonitrile and the reaction is refluxed for 3.5 hours. Chromatography afforded the title compound as a dark red foam in 81% yield. ¹ H-NMR (CDCl 3): δ 10.11 (bs, 1H), 8.52 (dd, J = 1.8 and 8.4 Hz, 1H), 8.43 (1.8 and 4.5) Hz,

1H), 8.33 (broad s, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.35 (d, J =

8.7 Hz, 1H), 7.26 (dd, J = 2.0 and 8.6 Hz, 1H), 7.03 (d, J = 2.1)

Hz, 1H), 6.74 (dd, J = 4.44 and 8.4 Hz, 1H), 3.21-3.12 (m, 2H),

2.68-2.58 (m, 1H), 2.54-2.46 (m, 1H), 2.47 (s, 3H), 2.28-2.18 (m, 1H), 1, 89-1.73 (m, 2H), 1.73-1.54 (m, 2H); ¹³ C-NMR (CDCl 3)

5: 155.7, 151.5, 135.5, 134.3, 129.5, 128.2, 128.1, 123.1,

119.4, 114.3, 113.0, 111.4, 66.7, 57.5, 40.8, 31.5, 29.9, 21.9.

Analysis calculated for C 19 H 21 N 5 O 2 · 1/3 H2O: C, 63.85; H, 6.11; N, 19.59; Found: C, 63.86; H, 5.86; N, 19.31.

K. 6- [3- (2-Dimethylaminoethyl) -indol-5-ylamino] -purin

5-Amino-3- (2-dimethylaminoethyl) indole and 6-chloropurine are used. No base was used, acetic acid was used as the solvent, and the reaction was refluxed at 116 ° C for 15 hours. Chromatography affords the title compound as a white foam in 66% yield. Melting point: 175 DEG C. (dec.). ¹³ C-NMR (CD3OD) δ • · · ·

153.7, 153.4, 141, 5, 136.0, 131.5, 128.3, 125.6, 119.2, 113.3,

109.9, 59.1, 43.6, 21.9.

Analysis calculated for C 17 H 19 N 7 · 1HCl · 2H ₂ O: C, 51.84; H, 6.14; N, 24.89. Found: C, 52.14; H, 6.22; N, 25.03.

L. (R, S) -3- (N-Methyl-pyrrolidin-3-yl) -5- (3-nitro-pyrid-2-yl-amino) -1H-indole (R, S) -3- ( N-methylpyrrolidin-3-yl) indole and 2-chloro-3-nitropyridine are used. The base is sodium acetate, the solvent is acetic acid, and the reaction is refluxed for 4 hours. Chromatography afforded the title compound as a dark red foam (44%). Melting point: 55.0-57.0 ° C. ¹³ C-NMR (CDCl 3): δ

155.7, 151.5, 135.5, 135.0, 129.0, 128.1, 127.1, 121.7, 119.3,

119.2, 114.7, 113.0, 111.6, 62.8, 56.2, 42.4, 35.1, 32.1; FAB LRMS (m / z, relative intensity) 306 (MH ⁺ , 100), 155 (38).

analysis · Results of Ci3HigN5O _{2 1/2} 2C4H4O [ethyl acetate] Based on: calculated : C% = 62.98, H, 6.08. N% = 18.36; found: C, 62.71; H, 5.80; N% = 18.51.

M. 3- (2-Dimethylaminoethyl) -5- (6-ethoxycarbonyl-3-methylthio-1,2,4-triazin-5-ylamino) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) indole and 6-ethoxycarbonyl-5-chloro-3-methylthio-1,2,4-triazine [Pesson, M. et al., Eur. J. Med. Chem., 269 (1972)]. The base was triethylamine and the solvent was tetrahydrofuran, and the reaction was stirred for 1 hour at room temperature. Chromatography affords the title compound as an orange solid (53%). Melting point: 197.0-199.0 ° C (foam). ¹³ C-NMR (DMSOd ₆ ) δ 5 173.2, 165.5, 150.5, 133.9, 132.5, 127.7, 127.1, 123.9,

116.8, 113.0, 112.2, 111.5, 62.0, 60.0, 45.2, 23.1, 14.0, 13.2;

LRMS (m / z, relative intensity) 400 (M ⁺ , 11), 386 (5), 195 (11),

163 (13), 58 (100).

Analysis for C ^ S ^ gH ^ NGC based · 0.3H ₂ O Calculated: C% = 56.22, H% = 6.11, N% = 20.70; Found: C, 56.50; H, 5.89; N, 20.33.

N. 5- (Benzoxaz-2-ylamino) -3- (2-dimethylaminoethyl) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) indole and 2-chlorobenzoxazole are used. No base was used, acetic acid was used as solvent, and the reaction was heated to reflux (116 ° C) for 2 hours under reflux. Chromatography afforded the title compound as a pale yellow foam (24%). ⁴³ C-NMR (CDCl 3): δ 160.5, 148.1, 142.7, 133.8, 130.0, 127.8, 124.0, 123.1, 121.0,

116.4, 116.4, 113.6, 111.8, 110.6, 108.9, 60.1, 45.3, 23.4; LRMS (m / z, relative intensity): 320 (M ⁺ , 33), 262 (15), 101 (12), 86 (33), 58 (100).

Calcd for C, gH ^ ^^ O · 1 / 4H ₂ O Calculated: C% = 70.23, H% = 6.36, N% = 17.24; Found: C, 70.53; H, 6.46; N, 17.06.

She. 5- (l-phenyl-tetrazol-5-yl-amino) - (2-dimethylamino-ethyl) -lH-indole

5-Amino-3- (2-dimethylaminoethyl) indole and 5-chloro-1-phenyl-α-tetrazole are used. Sodium carbonate as a base, soluble · ·

Absolute ethanol (29) was used and the reaction was heated to reflux (78 ° C) for 48 hours. After chromatography, the residue was triturated with chloroform to give the title compound as a white solid (7%). Melting point: 187.0188.0 ° C. 1 H-NMR (CD ₃ OD) δ 7.73 (d, J = 19 Hz, 1H), 7.56-7.52

(m, 3H), 7.29- 7.22 (M, 3H), 7.20 (dd, J = 2.0 and 8.6 Hz, 1H), 6.98-6.95 (m, IH), 4.93 (S, 2 H) , 2.96-2.91 (m, 2H), 2.66- • 2.59 (m, 2H), 2.27 (S, 6H); FAB LRMS (m / z, relative intensity) 348

(MH ⁺ , 100), 309 (23): HRMS calcd for C19H21N7:

347.1861, found: 347.1867.

Analysis for C19H21N7 · 2/3 CHCl3 (chloroform):

Found: C, 55.33; H, 4.64; N, 22.96;

Found: C, 55.5; H, 4.94; N, 23.33.

P. 5- (3-Benzylthio-1,2,4-thiadiaz-5-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole (R) -5 -Amino-3- (N-methylpyrrolidin-2-ylmethyl) -indole and

3-Benzylthio-5-chloro-1,2,4-thiadiazole is used. Sodium acetate was used as base, acetic acid was used as solvent and the reaction was refluxed for 1.5 hours. Purification by column chromatography afforded the title compound as an amorphous solid in 9% yield. ¹ H-NMR (CD 3 OD) δ 7.67 (bs, 1H), 7.40-7.17 (m, 6H), 7.09 (s, 1H), 7.04 (dd, J = 8, 6 and 2.1 Hz, 1H), 4.88 (broad s, about 3H), 4.40 (s, 2H), 3.16-3.03 (m, 2H), 2.60-2.37 (m, 2H), 2.43 (s, 3H), 2.25-2.19 (m, 1H), 1.83-1.50 (m, 4H); ¹³ C-NMR (CD 3 OD) δ 169.0, 139.1, 135.7, 133.1, 130.1, 129.5, 129.2,

128.3, 125.3, 116.3, 113.8, 113.2, 110.8, 68.4, 58.3, 41.1,

36.8, 32.4, 30.4, 22.4. HRMS calcd for C23H25N5S2 435.1555, found 435.1518.

Calcd for C23H25N5S2 · 0.4 NH ₃ O: Calculated: C% = 62.50, H% = 5.75, N% = 17.11; Found: C, 62.93; H, 5.50; N, 17.57.

Q. 3- (2-Dimethylaminoethyl) -5- (pyrimidin-2-ylamino) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) -1H-indole and 2-chloropyrimidine are used. Sodium acetate was used as base, acetic acid was used as solvent and the reaction was refluxed for 12 hours. Purification by column chromatography gave the title compound as a yellow solid (11%). ¹³ C-NMR (CD 3 OD) δ

162.6, 159.2, 135.4, 132.2, 128.9, 124.0, 118.6, 113.7, 112.6,

112.4, 112.3, 61.3, 45.4, 24.3; HRMS calcd for C ₁₆ H ₁₉ N ₅ : 281.1642; found: 281.1660.

Analysis results for the formula C2H4O2 (acetic acid)

Based on: date: C % = 65.62, H % = 6.80, N % = 22.51; found: C % = 65.74, H % = 6.68, N % = 22.60.

R. 3- (2-Dimethylaminoethyl) -5- (3-methylsulfonylpyrid-2-ylamino) -1H-indole

5-Amino-3- (2-dimethylaminoethyl) -indole and 2-chloro-3-methylsulfonylpyridine are used. The base is 2,6-lutidine, the solvent is bromobenzene and the reaction is refluxed for 3.5 hours. After column chromatography, the title compound is obtained in 13% yield as a yellow solid.

- 31 bans. Melting point: 66.0-68.0 ° C; ¹ H-NMR (CDCl ₃ ): δ 8.46 (s, NH),

8.33 (dd, J = 4.8 and 1.9 Hz, 1H), 8.33 (broad s, NH), 8.06 (dd, J = 7.8 and 1.9 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.29 (d,

J = 8.5 Hz, 1H), 7.20 (dd, J = 8.6 and 2.0 Hz, 1H), 6.97 (d, J =

2.2 Hz, 1H), 6.78 (dd, J = 7.8 and 4.8 Hz, 1H), 3.15 (s, 3H),

2.94-2.88 (m, 2H), 2.66-2.60 (m, 2H), 2.34 (s, 6H); HRMS:

calcd for C 18 H 22 ^N 4 ° 2 ^s : 358.1459; found:

358.1490.

S. 3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (2-nitrophenylamino) -1H-indole (R) -5-Amino-3- (N-methylpyrrolidin 2-ylmethyl) -indole and o-nitrofluorobenzene are used. The base is triethylamine, the solvent is o-nitrofluorobenzene and the reaction is refluxed for 24 hours. Column chromatography gave the title compound as a red amorphous solid (48%). ¹ H-NMR (CDCl ₃ ): δ S 9.62 (bs, NH), 8.77 (bs, NH), 8.19 (dd, J = 8.7 and 1.5 Hz, 1H). , 7.47 (d, J =

1.6 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.29-7.23 (m, 1H), 7,097.00 (Π, 3H), 6.69-. 6.64 (m, 1H), 3.20-3.12 (m, 2H), 2.63 (dd, J = 14.0 and 9.5HZ, 1H), 2.54-2.45 ( m, 1H), 2.45 (s, 3H), 2.25 (dd, J = 17.1 and 9.2 Hz, 1H), 1.91-1.54 (m, 4H); ¹³ C NMR (CDCl ₃ ): δ 145.4, 135.7, 134.8, 132.1, 130.1, 128.6, 126.5,

123.6, 120.7, 116.4, 116.4, 116.1, 114.1, 112.2, 66.7, 57.5,

40.8, 31.5, 29.8, 21.9; FAB HRMS calculated for [C 20 ^H 22 O 2 ^N 4 O: 351.1823; found: 351.1797.

• · 4 · 4

Τ. 5- (6-Methoxy-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -ΙΗ-indole (R) -5-Amino-3- ( N-methylpyrrolidin-2-ylmethyl) -indole and

2-Chloro-6-methoxy-3-nitropyridine was used. The base is triethylamine and the solvent is absolute ethanol and the reaction is refluxed for 5.5 hours. Column chromatography gave the title compound as a red, amorphous solid (54%). ³ H-NMR (CDCl 3): δ 8.80 (bs, NH), 8.37 (d, J = 9.1 Hz, 1H), 7.85 (s, 1H), 7.34-7, 28 (m, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.14 (d, J = 9.1 Hz, 1H), 3.85 (s, 3H), 3.193, 11 (m, 2H), 2.61 (dd, J = 13.8 and 9.5 Hz, 1H), 2.54-2.45 (m, 1H), 2.45 (s, 3H), 2 , 24 (dd, J 17.1 and 9.3 Hz, 1H), 1.91-1.54 (m, 4H); ¹³ C NMR (CDCl 3): δ 166.9, 151.3, 138.2, 134.0, 129.6,

127.8, 123.3, 122.0, 118.6, 114.1, 113.3, 111.1, 102.0, 66.5,

57.5, 54.7, 40.8, 31.6, 29.9, 21.9; HRMS: Calcd. For C20H23N5O3: 381.1803; found: 381.1799.

ü. 5- (4-Methyl-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole (R) -5-Amino-3- ( N-methylpyrrolidin-2-ylmethyl) -indole and

2-Chloro-4-methyl-3-nitropyridine was used. The base is triethylamine and the solvent is absolute ethanol and the reaction is refluxed for 24 hours. After column chromatography, the title compound is obtained in 34% yield as a red amorphous solid. ³ H-NMR (CDCl 3): δ 9.26 (bs, NH), 8.79 (bs, NH), 8.10 (d, J = 4.8 Hz, 1H), 7.64 (d , J = 1.7 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.5 and 1.9 Hz, 1H),

6.97 (d, J = 2.2 Hz, 1H), 6.56 (d, J = 4.8 Hz, 1H), 3.25-3.16

(m, 2H), 2.67 (dd, J = 13.2 and 9.4 Hz, 1H), 2.64-2.56 (m , 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.30 (dd, J = 17.7 and 9.4 Hz , 1H), 1.90-1.60 (m, 4H); ¹³ C NMR (CDCl3): 8 152.2, 151.5, 146.6, 134.3, 131.0, 130.0, 127.9, 123.4, 119 , 4, 117.1, 114.0, 113.3, 111.6, 67.0, 57.4, 40.7, 3 1.4, 29.5, 21.8, 21.7; FAB HRMS:

calculated for [ε ₂ ο ^Η 23 ^Ν 5 ° 2 ' ^H J: 366.1932; found:

366.1957.

V. 3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-5-phenyl-pyrid-2-ylamino) -1H-indole (R) -5-Amino-3 - (N-Methylpyrrolidin-2-ylmethyl) -indole and 4-bromo-3-nitrobiphenyl are used. Triethylamine was used as base, Ν, Ν-dimethylformamide as solvent and the reaction was continued at 110 ° C for 12 hours. Column chromatography gave the title compound as a red amorphous solid (24%). 1 H-NMR (CDCl ₃ ): δ = 9.63 (bs, NH), 8.97 (bs, NH), 8.42

(d, J = 2.2 Hz, 1H), 7.56 to 7, 25 (m, 9H), 7.08 (d, J = 9.0 Hz, 2 H) , 3.50-3.32 (m, 2H), 2.95 -2.79 (m, 2H) , 2.59-2.52 (m, 1H), 2.53 (S, 3H), 2,05- 1.71 (m, 4H); ¹³ C-NMR (CDCl 3): δ 144.4, 138.8 , 134.9, 134.5, 132.4, 131.1, 130.2, 129.7, 129.0, 127.3, 126.2 , 124.7, 124.1, 120.8, 116.7, 115.9, 112.7, 112.0, 67.9, 57.4, 40.6, 31.2, 28.6, 21.9; FAB HRMS: calcd [C26 H26 ^h ₄ ^h O2] formula Based on: 427.2136; found: 427.2099.

W. 5- (3-Cyanopyrid-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole (R) -5-Amino-3- (N- methylpyrrolidin-2-ylmethyl) -? - indole and

2-Chloro-nicotinonitrile was used. Sodium carbonate was used as base, N, N-dimethylformamide as solvent and the reaction was continued at 110 ° C for 20 hours. After separation by column chromatography, the title compound is obtained in 32% yield as an orange amorphous solid. R f = 0.4 in 9: 1: 0.1 methylene chloride: methanol: ammonium hydroxide. ¹³ C-NMR (CDCl 3): δ 157.7, 152.7,

141.7, 134.2, 129.8, 128.1, 123.1, 122.2, 118.7, 116.8, 113.6,

113.2, 111.5, 102.2, 66.6, 57.5, 40.8, 31.5, 30.0, 21.9; FAB HRMS: Calculated for [C 20 H 21 N 5 * H]: 332.2073; found: 332.1871.

X. 5- (6-Isopropoxy-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole (R) -5-Amino-3 - (N-Methylpyrrolidin-2-ylmethyl) -indole and 2,6-dichloro-3-nitropyridine are used. No base is used, 2-propanol is used as solvent. After stirring at room temperature for 1 hour, a solution of 5 equivalents of sodium hydride in 2-propanol was added dropwise with cooling to 0 ° C. The resulting mixture was stirred at room temperature under nitrogen for 2.5 hours and then concentrated in vacuo. Column chromatography of the residue afforded the title compound as an orange, amorphous solid (42%). ¹ H-NMR (CDCl 3): δ 10.6 (bs, NH), 8.57 (bs, NH), 8.37 (d, J = 9.2 Hz, 1H), 7.71 (s) , 1H), 7.34-7.28 (m, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.08 (d, J = 9.2 Hz, 1H), δ , 14 (Sept., J =

6.2 Hz, 1H), 3.18-3.10 (m, 2H), 2.61 (dd, J = 14.0 and 9.4 Hz, 1H), 2.54-2.45 (m , 1H), 2.44 (s, 3H), 2.23 (dd, J = 17.2 and 9.3 Hz, 1H), 1.90-1.53 (m, 4H), 1.25 ( d, J = 6.1 Hz, 3H), 1.24 (d, J • · · «· ·

V = 6.2 Hz, 3H); ¹³ C-NMR (CDCl ₃ ) δ 166.3, 151.8, 138.1, 134.1,

129.5, 127.9, 123.1, 121.7, 119.2, 114.2, 113.9, 111.0, 102.8, 70.4, 66.4, 57.5, 40, 8, 31.5, 29.9, 21.9, 14.0, 11.0; FAB HRMS:

calculated for [ε ₂ 2 ^Η 27 ^Ν 5 ° 3: 410.2194; found: 409.2187.

Y. 5- (4-Cyano-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole (R) -5-Amino-3- (N- methylpyrrolidin-2-ylmethyl) -? - indole and

4-Chloro-3-nitrobenzonitrile was used. Triethylamine was used as base and absolute ethanol was used as solvent and the reaction was refluxed for 4 hours. After separation by column chromatography, the title compound is obtained in 80% yield as a red solid. Melting point: 170-171 ° C; ¹³ C-NMR (CDCl 3): δ 147.3,

137.1, 135.4, 132.0, 131.4, 128.6, 128.0, 125.3, 120.6, 117.9,

117.1, 116.3, 113.1, 111.9, 99.1, 68.1, 57.3, 40.6, 31.2, 28.1,

21.9.

Analysis for C21 H21 N5 O2 · 0.05 0,0 ₂ εΐ ₂ Calculated: C, 66.59; H, 5.60; N, 18.44;

Found: C, 66.56; H, 5.26; N, 18.42.

Z. 3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (4-trifluoromethyl-2-nitrophenylamino) -1H-indole (R) -5-Amino-3- ( N-methylpyrrolidin-2-ylmethyl) -indole and 4-chloro-3-nitrobenzotrifluoride are used. The base is triethylamine and the solvent is absolute ethanol and the reaction is refluxed for 4.5 hours. Column chromatography gave the title compound as a red foam (38%).

Rf = 0.30 in 9: 1: 0.1 methylene chloride: methanol: ammonium hydroxide. ¹³ C-NMR (CDCl ₃ ): δ 5 147.0, 139.7, 135.1, 131.6, 131.0, 129.2, 128.5, 124.7, 124.2, 120.7 , 118.6, 116.8, 116.6,

113.6, 112.6, 67.1, 57.4, 40.8, 31.3, 29.2, 21.9. FAB LRMS 419 [MH +].

Calcd for C21H21F3N4O2 · 0.6 _CH2 C12 ratings O: Calculated: C% = 55.27, H% = 4.77, N% = 11.94; Found: C, 55.44; H, 4.58; N, 11.52.

ΑΆ. 5- (5,6-Dichloro-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole (R) -5-Amino-3- (N- methylpyrrolidin-2-ylmethyl) -1H-indole and

1,2,3-trichloronitrobenzene is used. Sodium carbonate was used as base, Ν, Ν-dimethylformamide as solvent and the reaction was continued at 125 ° C for 3 hours. After column chromatography, the title compound was obtained in 60% yield as a red solid. Rf = 0.4 (9: 1: 0.1 methylene chloride: methanol: ammonium hydroxide). 1 H-NMR (CDCl 3): δ = 8.59 (bs, NH), 8.36 (bs, NH), 7.96 (d, J = 9.1 Hz, 1H), 7.23 (d , J = 8.6 Hz,

1H), 7.09 (S, 1H), 7.07 (d, J = 9, 1 Hz, 1H), 6.99 (d, J - 1.9 Hz, 1H), 6.81 (Dd, J = 8.6 and 2.1 Hz, 1H), 3.15-3.05 (M, 2 H) , 2.54 (Dd, J = 13.8 and 9 , 6 Hz, 1H), 2.46-2.33 (m, 1H), 2.40 (S, 3H), 2.22 (Dd, J = 17.4 and 9.3 Hz, 1H), 1.84-1.48 (m, 4H); FAB

HRMS: Calculated for [C ₂₀ ^{H 20} O 2 ^Cl 2 ^N 4 ° 2 ' ^H J: 419.1044; found: 419.1046.

BB. 5- (5-Chloro-2-nitro-phenylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole (R) -5-Amino-3- (N-methyl- pyrrolidin-2-ylmethyl) -? - indole and

2,4-Dichloro-nitrobenzene is used. Sodium carbonate was used as base, Ν, Ν-dimethylformamide as solvent and the reaction was continued at 125 ° C for 3 hours. After column chromatography, the title compound was obtained as a red solid in 50% yield. FAB HRMS: Calculated for [ ^C 20 ^H 21 ^ClN 4 ^O 2: 385.1434; found: 385.1451.

CC. 5- (4-Cyano-2-nitrophenylamino) -3 - [(2R, 4R) -N-methyl-4-methoxypyrrolidin-2-ylmethyl] -1H-indole

5-Amino-3 - [(2R, 4R) -N-methyl-4-methoxypyrrolidin-2-ylmethyl] -1H-indole and 4-chloro-3-nitrobenzonitrile are used. The base was triethylamine and the solvent was absolute ethanol and the reaction mixture was refluxed for 3.5 hours. After column chromatography, the title compound was obtained as a red amorphous solid in 56% yield. 1 H-NMR (CDCl ₃ ): δ 9.92 (bs, NH), 8.54 (d, J

1.9 Hz, 1H), 8.52 (br s, NH), 7.45-7.39 (m, 3H), 7.13 (br s, 1H), 7.03 (dd, J = 8 , 8 and 1.7 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 3.80-3.70 (m, 1H), 3.26 (s, 3H), 3 , 25-3.15 (m, 2H), 2.70 (dd, J = 14.2 and 9.5 Hz, 1H), 2.49-2.38 (m, 1H), 2.42 (s

H), 2.25 (dd, J = 10.8 and 5.3 Hz, 1H), 2.19-2.10 (m, 1H), 1.671.56 (m, 1H); ¹³ C NMR (CDCl ₃ ): δ 147.2, 137.0, 135.1, 132.1,

131.1, 128.5, 128.0, 124.1, 120.3, 118.0, 117.0, 116.8, 114.0,

112.6, 99.0, 78.5, 65.9, 62.4, 56.5, 40.6, 39.2, 29.5; FAB HRMS: Calculated for [ ^C 22 ^H 23 ^N 5 ° 3: 406.1881; found: 406.1872.

Example 2

General Procedure for Alkylation of (R) -5- (3-Nitropyrid-2-ylamino) -3- (pyrrolidin-2-ylmethyl) -1H-indole

0.337 g (1.00 mmol) of (R) -5- (3-nitropyrid-2-ylamino) -3- (pyrrolidin-2-ylmethyl) -1H-indole and 0.126 g, 1.25 mmol To a solution of 1.25 equivalents of triethylamine in 10 ml of anhydrous methylene chloride or anhydrous acetonitrile or absolute ethanol or isopropanol, 1.25 mmol of the alkylating agent is added dropwise under nitrogen atmosphere. The resulting reaction mixture was stirred under nitrogen atmosphere at room temperature or refluxed for 1-20 hours depending on the substrate. The resulting reaction mixture was directly applied to a chromatographic column, which was loaded with about 25 g of silica gel and eluted with 9: 1: 0.1 methylene chloride: methanol: ammonium hydroxide. The title compound is obtained.

Using this procedure, the following compounds were prepared:

A. (R) -3- (N-Cyclopropylmethyl-pyrrolidin-2-ylmethyl) -5- (3-

nitro-pyridin-2-ylamino) -lH-indole

The reaction is carried out using methylene chloride as the solvent and bromomethylcyclopropane as the alkylating agent and refluxing for 4 hours. Chromatography afforded the title compound as a dark red foam (34%). ¹³ C-NMR (CDCl 3) δ 155.7, 151.4, 135.5,

134.3, 129.4, 128.2, 123.1, 119.3, 114.4, 114.3, 113.0, 111.4,

65.0, 59.9, 55.0, 30.9, 30.3, 22.2, 10.0; FAB LRMS (m / z, relative intensity): 392 (MH ⁺ , 33), 374 (3), 307 (3), 267 (7), 220 (7),

154 (10), 124 (100); HRMS calculated for _C2 2H25 5 ° ^N 2 O: 391.2011; found: 391.1988.

B. (R) -5- (3-Nitro-pyrid-2-ylamino) -3- [N- (2-propynyl) -

pyrrolidin-2-ylmethyl] indole

During the reaction, methylene chloride was used as solvent, propargyl bromide was used as alkylating agent at room temperature for 2 hours and the reaction mixture was stirred. After chromatography, the title compound was obtained as a dark red foam. ¹³ C-NMR (CDCl 3) δ

155.7, 151.4,

135.5,

134.3,

129.4, 128.0, 123.1, 119.2,

H4.3,

114.0, 113.0,

111.3, 79.1,

72.8, 61.6, 53.2,

40.8,

31.2,

29.8,

21.9; FAB LRMS (m / z, relative intensity): 376 (MH ⁺ ,

67),

350 (5), 307 (17), 267 (12), 220 (10), 136 (100);

HRMS:

calculated for C21H21N5O2:

375.1697; found:

375.1585.

C. (R) -5- (3-Nitro-pyrid-2-ylamino) -3- [N- (2-propenyl) -

pyrrolidin-2-ylmethyl] indole

The reaction was carried out using methylene chloride as solvent and allyl iodide as alkylating agent and stirring at room temperature for 2.5 hours. Chromatography afforded the title compound as a dark red foam in 59% yield. ¹³ C-NMR (CDCl 3) δ 155.7, 151.2, 135.6, 134.2, 129.9,

128.2, 126.9, 126.6, 125.6, 125.1, 119.6, 113.4, 112.2, 109.6,

67.4, 56.3, 53.7, 30.7, 27.2, 22.0; FAB LRMS (m / z, relative intensity): 378 (MH ⁺ , 100), 336 (3), 267 (10), 220 (13), 136 (40).

Analysis for C21H23N5O2 · 1.6 CHCl3 (chloroform):

• · · »4 · · • 4

Calculated: C, 47.75; H, 4.36; N, 12.32. Found: C, 47.89; H, 4.51; N, 12.68.

HRMS: Calcd. For C21H23N5O2: 377.1854; found: 377.1881.

D. (R) -5- (3-Nitro-pyrid-2-ylamino) -3- (N-propyl-pyrrolidin-2-ylmethyl) -1H-indole

The reaction is carried out using methylene chloride as solvent and propyl iodide as alkylating agent and stirring at room temperature for 18 hours. Chromatography afforded the title compound as a dark red foam (26%). ¹³ C-NMR (CDCl ₃ ) δ 155.6, 151.2, 135.5, 134.2, 130.0,

128.2, 126.8, 125.2, 119.7, 113.3, 113.1, 112.2, 109.6, 69.3,

56.9, 54.5, 30.6, 27.1, 22.0, 18.7, 11.4; FAB LRMS (m / z, relative intensity) 380 (MH ⁺ , 80), 363 (3), 333 (5), 271 (6), 243 (8),

157 (60), 135 (43), 112 (100); EI LRMS (m / z, relative intensity) 379 (M ⁺ , 0.2), 378 (1), 267 (3), 220 (5), 128 (14), 112 (100); HRMS: Calcd. For C21H25NO2: 379.2011; found: 379.2027.

E. (R) -3- (N-Butyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole

The reaction is carried out in methylene chloride using butyl iodide alkylating agent, and the reaction mixture is stirred at room temperature for 18 hours. Chromatography affords the title compound as a dark red foam (33%). ¹³ C-NMR (CDCl 3) δ 155.7, 151.2, 135.5, 134.2, 130.0, 128.2,

126.8, 125.2, 119.7, 113.3, 113.2, 112.2, 109.5, 69.2, 55.0,

54.5, 30.6, 27.1, 26.8, 22.0, 20.0, 13.3; LRMS (m / z, relative intensity) 393 (M ⁺ , 0.2), 392 (1), 391 (1), 267 (2), 220 (3), ·

- 41,126 (100); HRMS calcd for ^C 22 ^H 27 ^N 5 ° 2:

393.2167; found: 393.2156.

F. 3- [N- (2-Hydroxy-cyclopentyl) -pyrrolidin-2-ylmethyl] -5-

- (3-Nitropyrid-2-ylamino) -1H-indole

The reaction is carried out in methylene chloride, using cyclopentene oxide as the alkylating agent, and the reaction mixture is refluxed for 20 hours (82 ° C). Chromatography affords the title compound as a dark red foam (57% yield) which is a diastereomeric mixture of carbon atoms adjacent to the alcoholic group. ¹³ C-NMR (CDCl ₃ ) δ 155.6, 151.3, 135.5, 134.2, 129.3, 128.1, 123.3,

123.2, 119.0, 118.9, 114.6, 114.2, 114.2, 113.0, 111.4, 111.4,

75.5, 74.7, 70.6, 69.1, 62.4, 61.7, 51.1, 48.2, 34.6, 32.8,

31.1, 30.9, 30.8, 30.3, 29.2, 23.1, 23.0, 22.7, 21.7, 20.5; LRMS (m / z, relative intensity) 421 (M ⁺ , 0.2), 420 (1), 419 (1), 418 (55), 380 (13), 348 (22), 279 (100), 218. (30), 169 (44), 154 (91); HRMS: Calcd. For C23H27N5O3: 421.2116; found: 421.2040.

G. (R) -3- (N-Ethyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-yl-amino-1H-indole

The reaction is carried out in acetonitrile using ethyl iodide alkylating agent and the reaction mixture is stirred at room temperature for 7 hours. Chromatography affords the title compound as a dark red foam (32%). ¹³ C NMR (CDCl 3) δ 155.6, 151.2, 135.5, 134.2, 130.0, 128.2, 126.8,

125.2, 119.7, 113.3, 113.2, 112.2, 109.5, 68.8, 53.8, 50.1,

30.7, 27.2, 21.9, 10.5; FAB LRMS (m / z, relative intensity) 366 (MH ⁺ , 100), 332 (8), 257 (8), 229 (15), 157 (55), 135 (37);

- 42 • · ·· ** ··· «· · ···· · ···

HRMS: Calcd. For ^{C 20 H} 23 ^N 5 ^O 2: 365.1854; found: 365.1836.

H. (R) -5- (3-Nitro-pyrid-2-ylamino) -3- (N-pentyl-pyrrolidin-2-ylmethyl) -1H-indole

The reaction is carried out in methylene chloride using a pentyl iodide alkylating agent and the mixture is stirred at room temperature for 18 hours. Chromatography afforded the title compound as a dark red foam (23%). ¹³ C-NMR (CDCl ₃ ) δ 155.6, 151.2, 135.5, 134.2, 130.0, 128.2,

126.8, 125.3, 119.7, 113.3, 113.1, 112.2, 109.6, 69.1, 55.2,

54.5, 30.7, 28.7, 27.2, 24.5, 22.0, 12.8, 13.7; FAB LRMS (m / z, relative intensity) 408 (MH ⁺ , 36) 327 (8), 136 (100); HRMS:

calcd for ^C 23 ^H 29 ^N 5 ^O 2: 407.2324; found:

407.2299.

I. (R) -3- [N- (2-Methoxy-ethyl) -pyrrolidin-2-ylmethyl] -5- (3-nitro-pyrid-2-ylamino) -1H-indole

The reaction was carried out in a 1: 1 mixture of acetonitrile and methylene chloride, using (2-bromoethyl) methyl ether and 1.25 mmol of sodium iodide as the alkylating agent and refluxing for 7 hours at 40 ° C. ). Chromatography affords the title compound as a dark red foam (32%). ¹³ C-NMR (CDCl 3) δ 155.7,

151.2, 135.5, 134.2, 129.8, 128.1, 126.9, 125.0, 119.6, 113.4,

113.3, 112.2, 109.4, 69.1, 66.9, 59.0, 55.4, 46.4, 29.9, 26.8,

22.0; LRMS (m / z, relative intensity) 395 (M ⁺ , 0.5), 394 (1), 348 (20), 267 (39), 220 (68), 128 (100); HRMS calcd for ^C 21 ^H 25 ^N 5 ^O 3 395.1960; found: 395.1940.

J. (R) -3- [N- (2-Cyanoethyl) pyrrolidin-2-ylmethyl] -5- (3-

nitro-pyridin-2-ylamino) -lH-indole

The reaction was carried out in absolute ethanol, acrylonitrile was used as the alkylating agent, no base was used and the reaction mixture was stirred at room temperature for 18 hours. Chromatography afforded the title compound as a dark red foam (27%). ³ H NMR (CDCl 3): δ 10.1 (bs, 1H), 8.52 (dd, J = 8.4 and 1.6 Hz, 1H), 8.44 (dd, J = 1.5) and 4.4 Hz, 1H), 8.19 (bs, 1H), 7.76 (bs, 1H), 7.38-7.27 (m, 2H), 7.09 (d, J = 1.5 Hz, 1H), 6.76 (dd, J = 4.5 and 8.3 Hz, 1H), 3.27-3.13 (m, 2H), 3.08-3.01 (m , 1H), 2.88-2.78 (m, 1H), 2.74-

2.49 (m, 4H), 2.32-2.22 (m, 1H), 1.90-1.57 (m, 4H); LRMS (m / z, relative intensity) 390 (M ⁺ , 17), 335 (5), 268 (54), 220 (24), 123 (100); HRMS calculated for C ₂ H ₂ O ₂ 2N6O:

390.1807; found: 390.1773.

K. (R) -3- [N- (2-Cyanomethyl) pyrrolidin-2-ylmethyl] -5- (3-

nitro-pyridin-2-ylamino) -lH-indole

The reaction is carried out in a 3: 2 mixture of acetonitrile and methylene chloride, bromoacetonitrile is used as alkylating agent and the reaction is stirred at room temperature for 18 hours. Chromatography afforded the title compound as a dark red foam (76%). ¹³ C-NMR (CDCl 3) δ 155.8, 151.4, 135.5, 134.2, 129.6, 128.1,

127.9, 123.3, 119.3, 115.5, 114.1, 113.1, 111.5, 62.1, 53.7,

40.7, 31.2, 29.9, 22.2 ,; LRMS (m / z, relative intensity) 376 (M ⁺ ,

6), 375 (28), 279 (58), 180 (10), 169 (14), 109 (100); HRMS calcd for ^C 20 ^R 20 ^R 6 ° 2 376.1650; found:

376.1641.

Example 3

General procedures are 5-arylamino-3- (piperidin-4-yl) -1H-indole derivatives, 5-arylamino-3- (1,2,5,6-tetrahydropyrid-4-yl) - 5-Aryl-amino-3- (N-tertiary) -indole derivatives and 5-aryloxy-3- (1,2,5,6-tetrahydropyrid-4-yl) -indole-derivatives butoxycarbonylpiperidin-4-yl) -1H-indole derivatives, 5-arylamino-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -1H by deprotection of indole derivatives and 5-aryloxy-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -1H-indoles

2.00 mmol 5-arylamino-3- (N-tert-butoxycarbonyl-piperidin-4-yl) -indole, 5-arylamino-3- (N-tert-butoxycarbonyl-1) , 2,5,6-tetrahydropyrid-4-yl)-)-indole or 5-aryloxy-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) - A solution of 1H-indole in 20 mL of absolute methanol was stirred and hydrogen chloride gas was bubbled at 0 ° C for about 15 minutes. The resulting mixture was stirred at 0 ° C under nitrogen for 6 hours and then filtered to give 5-arylamino-3- (piperidin-4-yl) -α-indole, 5-arylamino-3- (1). , 2,5,6-tetrahydropyrid-4-yl) -1H-indole or 5-aryloxy-3- (1,2,5,6-tetrahydropyrid-4-yl) -1H-indole hydrochloride- salt.

A. 5- (3-Nitro-pyrid-2-ylamino) -3- (piperidin-4-yl) -1H-indole

3- (N-tert-butoxycarbonylpiperidin-4-yl) -5- (3-nitropyrid-2-ylamino) -1H-indole is used. After filtration, the title compound was obtained in 83% yield as a dark red solid. Melting point: 220 ° C (dec.). ¹³ C-NMR (DMSO-d 6)?

155.5, 150.8, 135.7, 134.4, 129.2, 127.9, 126.0, 121.8, 119.3, ·· «·« ··· β

118.3, 114.5, 113.4, 111.5, 43.5, 31.0, 29.0. LRMS (m / z, relative intensity): 337 (M ⁺ , 31), 302 (44), 281 (31), 240 (100).

Analysis calculated for C 18 H 19 N 5 O 2 · 3.0 HCl: C, 48.39; H, 4.96; N, 15.68. Found: C, 48.73; H, 5.16; N, 15.21.

B. 5- (3-Nitro-pyrid-2-ylamino) -3- (1,2,5,6-tetrahydropyrid-4-yl) -1H-indole

3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (3-nitropyrid-2-ylamino) -1H-indole is used. Filtration gave the title compound as a dark red solid in 85% yield. Melting point: 204 DEG C. (dec.). ¹³ C-NMR (DMSO-d ₆ ) δ 155.3, 150.7, 135.7, 134.9, 130.5, 130.0,

128.1, 124.7, 124.3, 119.6, 115.7, 114.7, 113.5, 111.8, 48.6,

41.2, 23.9.

Analysis for ^C 18 ^H 17 ^N 5 ° 2 * ^{2 '75} HClOH ³ OH (methanol):

Found: C, 48.80; H, 5.12; N, 14.98;

Found: C, 49.11; H, 5.14; N, 15.34.

C. 5- (5-Nitro-pyrid-2-ylamino) -3- (1,2,5,6-tetrahydropyrid-4-yl) -1H-indole

3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (5-nitropyrid-2-ylamino) -indole is used. Filtration afforded the title compound as a dark red solid (87%). Melting point: 273 ° C (dec.). ¹³ C NMR (DMSO-d 6) δ 159.9, 146.7, 135.2, 134.2, 132.2, 131.9,

130.1, 124.5, 124.4, 118.0, 115.0, 113.0, 112.1, 41.9, 40.6,

24.7; LRMS (m / z, relative intensity): 336 (20), 335 (M ⁺ , 100);

306 (50), 294 (53), 167 (67).

• ··· ♦ ·· «

- 46 Analysis calculated for C ₃ H ₃₇ N ₅ O 2 · 2.1 HCl: C, 52.48; H, 4.67; N, 17.00; Found: C, 52.41; H, 4.54; N, 16.71.

D. 5- (3-Nitropyrid-2-yloxy) -3- (1,2,5,6-tetrahydropyrid-4-yl) -1H-indole

3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (3-nitropyrid-2-yloxy) -indole is used. After filtration, the title compound was obtained as a yellow solid (53%). M.p. 244.0-245.0 ° C; ^X3 C NMR (DMSO-d6) δ 155.9, 152.1, 146.2, 135.9, 134.8, 134.1, 129.7,

125.3, 124.6, 118.7, 116.2, 114.9, 112.7, 112.4, 112.3, 41.2,

24.0.

Analytical results based on the formula: CjgHig ^ Og · 1.5 HCl * O, 5 CH3OH (methanol):

Found: C, 54.59; H, 4.83; N, 13.76.

Found: C, 54.21; H, 4.56; N, 13.44.

E. 5- (5-Nitropyrid-2-yloxy) -3- (1,2,5,6-tetrahydropyrid-4-yl) -1H-indole

3- (N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-

- (5-Nitropyrid-2-yloxy) -? - indole is used. After filtration, the title compound was obtained as an orange foam in 19% yield. ¹³ C-NMR (DMSO-d 6) δ 167.7, 146.3, 144.9, 140.0,

135.5, 134.8, 129.7, 124.2, 115.5, 112.7, 112.3, 110.9, 44.7,

42.8, 28.1; LRMS (m / z, relative intensity): 336 (M ⁺ , 24), 307 (9), 210 (100), 185 (40); HRMS calcd for C ₁₈ H ₁₈ N ₄ O 3: 336.1224; found: 336.1196.

• · · · «« ν · * · • »» · * ν • ·· <«· <· • · · · · · · · · · · · · ·

Example 4

3- (2-Dimethylaminoethyl) -5- (3-aminopyrid-2-ylamino) -1H-indole

3.27 g (3.90 mmol) of 3- (2-dimethylaminoethyl) -5- (3-nitropyrid-2-ylamino) -1H-indole, 200 mg of 10% palladium on carbon and of ethanol (2 ml) was shaken under a hydrogen atmosphere (2.94 x 10 ⁵ Pa) for 2 hours. The reaction mixture was then filtered over diatomaceous earth, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (about 40 g). Absolute methanol was used as eluent. 0.74 g (64%) of the title compound is obtained in the form of an off-white solid. Mp 196.0-198.0 ° C (foam). ¹³ C-NMR (DMSO-d 6) δ 145.3, 134.5, 133.6, 132.1, 131.0, 127.3, 122.6,

118.8, 116.1, 114.2, 112.1, 110.8, 108.6, 60.1, 45.2, 23.4; HRMS calcd for C17H21N5 295.1793; found: 295.1810. Analysis calculated for C ₁₇ H 21 N ₅ · 0.4 C ₂ H ₈ O (ethanol): C, 68.13; H, 7.52; N, 22.32;

Found: C, 68.12; H, 7.19; N, 22.51.

Example 5

3- (2-Dimethylaminoethyl) -5- (3-phenylcarbonylaminopyrid-2-ylamino) -1H-indole

0.157 g, 0.53 mmol of 3- (2-dimethylaminoethyl) -5- (3-aminopyrid-2-ylamino) -indole and 74 μΐ, 0.54 mmol, 1.0 To a solution of the equivalent of triethylamine in 3 ml of anhydrous tetrahydrofuran was added 62 μΐ, 0.54 mmol, 1.0 equivalent of benzoyl chloride, with stirring. The resulting reaction mixture was stirred at room temperature under nitrogen for 15 minutes. To the mixture was then added 10 mL of saturated sodium bicarbonate solution.

48 and the aqueous mixture was extracted with ethyl acetate (3 x 10 mL). The organic extracts were combined, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (0.082 g, 39%) as an amorphous solid. ¹³ C-NMR (DMSO-d 6) δ

166.5, 151.9, 144.5, 134.5, 132.7, 132.5, 131.6, 128.3, 128.0,

127.2, 122.8, 119.6, 117.3, 113.3, 112.1, 110.8, 110.4, 59.9, 45.0, 23.1; LRMS (m / z, relative intensity): 399 (M ⁺ , 100), 354 (33), 249 (10), 235 (18), 204 (40), 160 (86); HRMS calculated a

For C24H25N5O: 399.2062; found: 399.2080.

Example 6

3- (2-Dimethylaminoethyl) -5- (6-benzylaminocarbonyl-3-methylthio-1,2,4-triazin-5-ylamino) -1H-indole

0.25 g (0.62 mmol) of 3- (2-dimethylaminoethyl) -5- (6-ethoxycarbonyl) -3-methylthio-1,2,4-triazin-5-ylamine ) -1H-Indole (0.14 mL, 1.25 mmol, 2.0 equivalents of benzylamine) was added dropwise to a stirred mixture of methylene chloride (5 mL) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature under nitrogen for 48 hours and then filtered. The resulting yellow solid was recrystallized from methanol: ethyl acetate (4: 1) to give the title compound (0.063 g, 22%) as a yellow solid. M.p. 207.0, 209.0 ° C; FAB HRMS calculated for [C24H27N5OS · Η ⁺ ] 462.2079, found:

462.2054.

Analysis: Calculated for C24H27N7OS · 3/4 H2O: C, 60.67; H, 6.05; N, 20.63. Found: C, 60.58; H, 5.73; N, 20.58.

Example 7

N-Methyl-3- (5-phenyl-butoxycarbonylamino-3-yl) succinamide

2.50 g (10.58 mmol) of 5-phenylcarbonylamino-1H-indole [Chem. Abstracts, 10991 g (1954)] and 2.94 g (26.46 mmol) of 2.5 equivalents of N-methyl maleimide in 75 mL of glacial acetic acid are refluxed for 24 hours. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in ethyl acetate (50 mL). This solution was washed with saturated aqueous sodium bicarbonate (2 x 25 mL), dried over magnesium sulfate, and concentrated in vacuo. The residual oil was purified by column chromatography using about 100 g silica gel, eluting with a gradient of ethyl acetate: hexane 1: 3 to 1: 1. This gave 1.06 g (29%) of the title compound as a white solid. Melting point: 226.5-

227.5 ° C; FAB LRMS (m / z, relative intensity): 348 (MH ⁺ , 100),

332 (2), 275 (4), 263 (5).

Analysis for C 20 H 17 ^N 3 O 3 · ⁸ / H ² O: Calculated: C, 68.71; H, 4.97; N, 12.02; Found: C, 68.68; H, 4.74; N, 11.91.

Example 8

5-Benzylamino-3- (N-methylpyrrolidin-3-yl) -1H-indole

A solution of N-methyl-3- (5-phenylcarbonylaminoindol-3-yl) succinamide (18.31 g, 52.71 mmol) in dry tetrahydrofuran (270 mL) was stirred at 0 ° C for 45 min. lithium aluminum hydride (20.01 g, 527 mmol, 10 equivalents) was added. The resulting reaction mixture was stirred at room temperature under nitrogen for 24 hours. The reaction mixture is then carefully added to the reaction mixture

50 g of sodium sulfate decahydrate followed by 5 ml of water and 100 ml of ethyl acetate. The resulting mixture was stirred at room temperature for 1 hour, then filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography over a silica gel column (about 500 g) eluting with a gradient of ethyl acetate: methanol: triethylamine 9: 0: 1 to 8: 1: 1. 7.90 g (49%) of the title compound are obtained as a pale yellow oil. ¹³ C-NMR (acetone-dg): δ 142.9,

142.1, 132.3, 129.3, 128.6, 127.5, 121.9, 118.6, 112.8, 112.5,

102.0, 63.6, 57.1, 49.9, 42.8, 36.5, 33.0; FaB LRMS (m / z, relative intensity): 306 (MH ⁺ , 100), 263 (4), 248 (4), 223 (8).

Example 9

5-Amino-3- (N-methylpyrrolidin-3-yl) -1H-indole

7.80 g, 25.5 mmol of 5-benzylamino-3- (N-methylpyrrolidin-3-yl) -1H-indole, 16.10 g, 255 mmol, 10 equivalents of ammonium formate and 0.78 g. A mixture of 10% palladium on carbon (10%) in 250 ml of absolute ethanol was heated at reflux for 1 hour under nitrogen. The reaction mixture was filtered, the filtrate evaporated in vacuo and the residue chromatographed on a column using about 200 g of silica gel using 0.3% triethylamine in methanol as eluent. Yield: 0.90 g (16%) of the title compound as a pale yellow oil. ⁴ H-NMR (CD 3 OD): δ 7.13 (d, J = 8.5 H 2, 1H), 6.94 (bs, 2H), 6.65 (dd, J = 2.0 and 8.5 Hz, 1H), 4.91 (s, 2-NH), 3.66-3.50 (m, 1H), 3.17-3.08 (broad t, 1H), 2.96-2.85 (m, 1H), 2.67-2.50 (m, 2H), 2.40 (s,

3H), 2.37-2.24 (m, 1H), 2.08-1.93 (m, 1H); FAB LRMS (m / z, relative intensity): 216 (MH ⁺ , 100).

Example 10 (R) -3- (N-Benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl) -5-dibenzylamino-1H-indole

To a mixture of (R) -N-benzyloxycarbonyl-proline (3.59 g, 14.41 mmol) in N, N-dimethylformamide (0.1 ml) in methylene chloride (45 ml) was added dropwise with stirring, 21.62 mmol,

1.5 equivalents of oxalyl chloride. The resulting foaming mixture was stirred at room temperature under nitrogen for 1.5 hours. The mixture was then evaporated to dryness in vacuo and the residue ((R) -N-benzyloxycarbonyl-proline acid chloride) dissolved in 50 ml of anhydrous ether. This solution was added dropwise to 9.00 g, 28.81 mmol, 2.0 equivalents of 5-dibenzylaminoindole and 10.08 mL, 30.25 mmol, 2.1 equivalents of ether. ethyl magnesium bromide in 75 ml of anhydrous ether, which was stirred at room temperature under nitrogen for 30 minutes before adding an ethereal solution of (R) -N-benzyloxycarbonyl-proline acid chloride. The resulting reaction mixture was stirred at room temperature under nitrogen for 30 minutes, then ethyl acetate (100 mL) and saturated sodium bicarbonate solution (75 mL) were added. The organic phase is removed and the aqueous phase is extracted with 100 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate and evaporated in vacuo. The resulting green oil was triturated with 50 ml of anhydrous ether to give the title compound as a white solid. Melting point: 176.0-177.0 ° C; LRMS (m / z, relative intensity): 543 (100, M ⁺ ), 453 (10), 407 (7), 339 (40), 307 (10), 247 (10), 154 (38); [α] ²⁵ = i, o);

+ 112 ° (THF, c

Analysis for C35H33N3O3: C, 77.32; H, 6.12; N, 7.73. Found: C, 77.35; H, 6.30; N, 7.66.

Example 11 (R) -5-Dibenzylamino-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole

To a mixture of lithium aluminum hydride (0.96 g, 25.2 mmol, 2.0 equiv.) In dry tetrahydrofuran (125 mL) at 0 ° C was added dropwise, with stirring, (R) -3- (N, 6.90 g, 12.69 mmol). benzyloxycarbonylpyrrolidin-2-ylcarbonyl) -5-dibenzylamino-1H-indole in 25 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature under nitrogen for 30 minutes, then 0.55 g (25.2 mmol, 2.0 equiv.) Of lithium borohydride was added and the mixture was refluxed under nitrogen for 6 hours (66 ° C). ). The mixture is then cooled, 1.5 ml of water, 1.5 ml of 20% sodium hydroxide solution and 4.5 ml of water are added successively. The resulting mixture was stirred at room temperature under nitrogen for 1 hour, filtered over silica and the filtrate evaporated in vacuo. The resulting 8.8 g of a green oil is dissolved in 90 ml of absolute ethanol and 8.0 g of cesium carbonate and 8.0 g of sodium carbonate are added. The resulting mixture was refluxed for 12 hours. The mixture was evaporated in vacuo and the residue partitioned between 50 mL of saturated aqueous sodium bicarbonate and 100 mL of ethyl acetate. The organic phase is removed and the aqueous phase is extracted with 100 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate and evaporated in vacuo. The resulting brown oil was purified by column chromatography using a silica gel column (about 200 g), eluting with a 9: 1: 0.1 mixture of methylene chloride, methanol and ammonium hydroxide. This gave 4.63 g (89%) of the title compound as a light green foam. ³ H-NMR (CDCl 3) ^: δ 7.82 (bs, NH), 7.35-7.19 (m, 10H), 7.20 (d, J = 8.6 Hz, 1H), δ, 95 (d, J = 2.1 Hz, 1H), 6.85 (dd, J = 2.3 and 8.7 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 4.65 (s, 4H), 3.25-3.02 (m, 2H), 2.52 (dd, J = 9.5 and 13.9 Hz, 1H), 2.39-2.15 ( m, 2H), 2.30 (s, 3H), 1.85-1.40 (m, 4H); ¹³ C-NMR (CDCl 3) δ 143.2, 139.7, 130.5, 128.5,

128.2, 127.3, 126.8, 122.9, 112.5, 112.2, 111.8, 103.4, 67.0, 57.4, 56.4, 40.6, 31, 4, 29.7, 21.9; HRMS calcd for C 28 H 31 N 3: 409.2520; found: 409.2475.

Example 12 (R) -5-Amino-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole

(R) -5-dibenzylamino-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole (1.08 g, 2.64 mmol) and palladium (II) hydroxide on carbon (0.6 g). ml of absolute ethanol was stirred and shaken at 40 ° C for 4 hours at 2.94 x 10 ⁵ psi hydrogen atmosphere. The resulting mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. 0.60 g (2.62 mmol) of the title compound is obtained in the form of a white foam. 1 H-NMR (DMSO-d 6) δ 10.65 (bs, NH), 7.14 (d, J = 2.2 Hz, 1H), 7.12 (d, J =

8.6 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 6.60 (dd, J = 2.0 and 8.6 Hz, 1H), 3.63-2, 83 (m, 7H), 2.78 (s, 3H), 2.05-1.67 (m, 4H);

[α] 25 = ₊ go (MeOH, c = 1.0); HRMS calcd for C 14 H 19 N 3: 229.1575; found: 229.1593.

Example 13 (R) -3- (N-Benzyloxycarbonyl-pyrrolidin-2-ylmethyl) -5-dibenzylamino---indole

A solution of (R) -3- (N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl) -5-dibenzylamino-1H-indole (1.50 g, 2.75 mmol) in dry tetrahydrofuran (30 mL) was stirred. 0.24 g (11.0 mmol, 4.0 equivalents) of solid lithium borohydride are added. The resulting mixture was refluxed for 4 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added and the mixture was stirred at room temperature for 30 minutes. This aqueous mixture was extracted with ethyl acetate (3 x 25 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography over silica gel (50 g) eluting with ethyl acetate / hexane (1: 3). This gave 1.02 g (70%) of the title compound as a white foam. FAB LRMS (m / z, relative intensity): 530 (MH ⁺ , 87); 529 (M ⁺ , 100), 439 (10), 409 (10), 325 (32), 235 (20).

Example 14 (R) -5-Amino-3- (pyrrolidin-2-ylmethyl) -1H-indole

(R) -3- (N-Benzyloxycarbonyl-pyrrolidin-2-ylmethyl) -5-dibenzylamino-1H-indole (7.90 g, 14.91 mmol) and palladium on carbon (3.16 g) -hydroxide (Pearlman's catalyst) in 100 ml of absolute ethanol was shaken for 12 hours at room temperature under a hydrogen gas pressure of 2.94 χ 10 ⁵ Pa. The resulting mixture was filtered through diatomaceous earth, the filtrate was evaporated and dried in vacuo. 3.2.20 g (100%) of the title compound are obtained in the form of a white foam. ¹ H NMR (CD 3 OD) δ 7.18 (d, J = 8.5 Hz, 1H), 7.08 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H),

6.69 (dd, J = 1.9 and 8.5 Hz, 1H), 3.81-3.69 (m, 1H), 3.30-2.95 (m, 4H), 2.09-. 1.55 (m, 4H); ¹³ C-NMR (CD ₃ OD) δ 5 140, 1, 133.4,

129.1, 125.0, 114.6, 113.1, 109.8, 105.1, 62.1, 46.0, 31.1,

29.1, 24.3; LRMS (m / z, relative intensity): 215 (M ⁺ , 2), 198 (1), 146 (100), 128 (7), 117 (9), 70 (60).

Example 15

General Procedure 3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (pyrid-2-ylamino) -1H-indole, 3- (N-tert-butoxy) -carbonyl-piperidin-4-yl) -5- (pyrid-2-ylamino) -1H-indole and 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) - 5-amino-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-indole, 5- (pyridin-2-yloxy) -indole, amino-3- (N-tert-butoxycarbonylpiperidin-4-yl) -ΙΗ-indole or 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) - By condensation of 5-hydroxy-1H-indole with 2-chloropyridine

10.0 mmol 5-amino-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-indole, 5-amino-3- (N-tert-butoxy) -carbonyl-piperidin-4-yl) -I-indole or 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-hydroxy-1H-indole and 12, To a solution of 0 nM, 1.2 equivalents of base in 35 ml of anhydrous tetrahydrofuran or dioxane was added 11.0 mmol, 1.1 equivalents of 2-chloropyridine. The resulting mixture is stirred for 3 to 48 hours at room temperature or under reflux, depending on the substrate and the solvent used. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 x 25 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column containing about 150 g of silica gel and eluted with the appropriate solvent system. Thus, the desired 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (pyrid-2-ylamino) -indole, 3- (N- tert-butoxycarbonylpiperidine-4-yl) -5- (pyrid-2-ylamino) -1H-indole or 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine); 4-yl) -5- (pyridin-2-yloxy) -α-indole is obtained.

Following this procedure, the following compounds were prepared:

A. 3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (3-nitropyrid-2-ylamino) -1H-indole

5-Amino-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -indole and 2-chloro-3-nitropyridine are used. The base was triethylamine, solvent was tetrahydrofuran, and the mixture was refluxed (66 ° C) for 8 hours, eluting with a gradient of diethyl ether to hexane (1: 1 to 1: 0). The title compound was obtained in a 73% yield as a dark red foam. ¹ H-NMR (CDCl 3): δ 10.1 (bs, 1H), 8.51 (dd, J = 1.8 and 8.4 Hz, 1H), 8.43 (dd, J = 1.8) and

4.5 Hz, 1H), 8.20 (bs, 1H), 8.00 (bs, 1H), 7.40-7.35 (m, 2H), 7.19 (d, J = 2 , 5 Hz, 1H), 6.75 (dd, J = 4.5 and 8.3 Hz, 1H), 6.12 (br m, 1H), 4.12 (br m, 2H), 3.66 (br t, J = 5.7 Hz, 2H), 2.55 (br m, 2H), 1.49 (s, 9H), TLC [diethyl ether]: R f = 0.4.

♦ · ·

Β. 3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (5-nitropyrid-2-ylamino) -1H-indole

5-Amino-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -indole and 2-chloro-5-nitropyridine are used. Triethylamine is used as base, tetrahydrofuran is used as solvent, and the reaction mixture is refluxed for 48 hours (66 and methylene chloride and hexane as the chromatographic solvent system).

A 1: 1 mixture is used. The title compound was obtained in% yield as a red foam.

¹ H-NMR (CD ₃ OD): δ 5.95 (d, J

2.4

Hz, 1H),

8.18 (dd, J = 2.8 and 9.3

Hz, 1H), 7.96 (s broad,

7.38 (d,

J = 8.9 Hz, 1H), 7.32 (s,

1 H), 7.24 (dd, J = 2.2 and 8.8)

Hz, 1H),

6.70 (d, J = 9.0 Hz,

1H),

6.10 (wide m, 1H), 4.89 (s,

2-NH);

4.08 (broad m, 2H),

3.65 (br t, J = 5.6 Hz, 2H), 2.56 (br m, 2H), 1.49 (s,

TLC [diethyl ether]: Rf = 0.45.

C. 3- (N-tert-Butoxycarbonylpiperidin-4-yl) -5- (3-nitropyrid-2-ylamino) -1H-indole

5-Amino-3- (N-tert-butoxycarbonylpiperidin-4-yl) -1H-indole and 2-chloro-3-nitropyridine are used. Triethylamine was used as base, dioxane as solvent, refluxed (101 ° C) for 5 hours, eluting with 30-40% ethyl acetate in hexane. The title compound was obtained in 70% yield as a dark red foam. ³ HNMR (CDCl 3): δ = 155.8, 155.0, 151.6, 135.5, 134.6, 129.4,

126.9, 121.3, 120.8, 119.8, 114.8, 113.1, 111.5, 79.4, 44.5,

33.6, 32.8, 28.5.

Analytical results based on the formula C23H27N5O4 · 1/4 C4HgC> 2 [ethyl acetate]:

• · · «

* calculated:

C, 62.73;

Η% = 6.36,

N, 15.24;

found:

C, 62.51;

Η% = 6.08,

N, 15.21.

D. 3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (3-nitropyrid-2-yloxy) -I-indole

3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-hydroxy-1H-indole and

2-Chloro-3-nitropyridine is used. The base is 60% oil in sodium hydride and the solvent is tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours, eluting with a gradient.

The title compound was obtained in 62% yield as a yellow solid.

Melting point:

206.0-208.0 ° C (foam).

¹ H-NMR (DMSO-d 6):?

8.53 (dd, J = 1.8 and 4.4 Hz,

7.62 (d,

J = 1.8 and 8.3 HZ, 1H), 8.33 (dd,

2.0 Hz, 1H), 7.50 (wide s, 1H), 7.42 (d (dd, J =  4.4 and 8.3 Hz, 1H), 6.94 (Dd, J 6.05 to 6, 01 (m, 1H), 4.02-3.94 (M, 2 H) , 3 Hz, 2H) , 2.54-2.45 (m, 2H), 1.42 (s, 9 H); raffia) [Methylene chloride / hexane 1: 1] : Rf =

, J = 8.6

2.0 and

Hz, 1H),

8.6 Hz,

7.30 (broad t, J = 5.6 (TLC); TLC (methylene chloride: hexane = 1: 1); Rf

0.2; TLC [diethyl ether]: _Rf = 0.3.

E. 3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5- (5-nitropyrid-2-yloxy) -1H-indole

3- (N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5

hydroxy-1H-indole and 2-chloro-5-nitropyridine are used. The base is 60% oily sodium hydride and the solvent is tetrahydrofuran. The reaction mixture was refluxed (66 ° C) for 12 hours, eluting with diethyl ether: hexane (1: 3). The title compound was obtained as a yellow foam in 78% yield. ¹ H-NMR (CD 3 OD): δ 8.88 (d, J = 2.8 Hz, 1H), 8.39 (dd, J = 2.8 and 9.1 Hz, 1H), 7.56 (d , J = 2.1 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.31 (s, 1H), 6.94-6.88 (m, 2H), δ , 98 (br m, 1H), 4.88 (s, NH), 4.00 (br m, 2H), 3.59 (br t, J = 5.3 Hz, 2H), 2.50 (br m, 2H), 1.44 (s, 9H); LRMS (m / z, relative intensity):

436 (M ⁺ , 4), 379 (68), 363 (16), 335 (29), 57 (100); TLC [methylene chloride / diethyl ether 1: 1]: Rf = 0.5.

Example 16

5-Amino-3- (N-tert-butoxycarbonyl-piperidin-4-yl) -lH-indole

3.55 g (10.34 mmol) of 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-nitro-1H-indole and 0.55 g, 10% palladium on carbon in 60 ml of absolute ethanol was shaken at room temperature for 7 hours 2.94 χ 10 ⁵ psi hydrogen atmosphere. The resulting mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The resulting oil was triturated with diethyl ether to give the title compound (2.56 g, 78%) as a light pink solid. Melting point: 215 DEG C. (dec.). ¹³ C NMR (CDCl 3): 155.0, 139.0, 131.3, 127.3, 120.4, 119.8, 112.9, 111.8, 104.1, 79.4, 44 5, 33.8,

32.7, 28.5.

H, 8.03; N, 13.13 Found: C, 67.57; H, 8.03; N, 13.13. Found: C, 67.20; H, 8.07; N, 13.44.

• 9

Example 17

General procedure for the preparation of 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -1H-indole derivatives from indole

To a solution of 2.51 g, 105 mmol, 7 equivalents of sodium in 5 ml of absolute methanol are added 15.0 mmol of indole and 8.96 g, 45.0 mmol, 3.0 equivalents of N- (tert-butoxycarbonyl) - 4-piperidone. The resulting mixture was under nitrogen atmosphere

Reflux for 3 to 24 hours (65 ° C), depending on the indole used. The resulting mixture was concentrated in vacuo and the residue partitioned between 50 mL of saturated aqueous sodium bicarbonate and 50 mL of ethyl acetate. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by trituration with diethyl ether or column chromatography. The desired 3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -α-indole is obtained.

Using the above procedure, the following compounds were prepared:

A. 5-Amino-3- (N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -1H-indole

5-Aminoindole was used, the reaction mixture was heated under reflux for 5 hours, and the residue was purified by chromatography on silica gel (200 g) using diethyl ether as eluent. The title compound was obtained as an off-white foam in 70% yield.

- 61 ^1H-NMR (CD3OD): <5 7.26 (d, J = 1.8 Hz, 1H), 7.17 (s, 1H), 7.15 (d, J = 8.9 Hz, 1H), 6.70 (dd, J = 2.0 and 8.5 Hz, 1H), 6.09-6.03 (m, 1H), 4.88 (s, 3H, interchangeable protons), 4, 12-4.06 (m, 2H), 3.63 (broad t, J = 5.1 Hz, 2H), 2.57-2.47 (m, 2H), 1.49 (s,

9H); TLC [diethyl ether]: Rf 0.2.

B. 3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-hydroxy-1H-indole

5-Hydroxyindole was used and the reaction was refluxed for 3 hours and the solid residue was triturated with diethyl ether (100 mL) to give the title compound as a white solid (88%). Melting point: 230 ° C (dec.). ¹³ C-NMR (DMSO-d 6) δ 154.0, 151.1, 131.5, 130.5, 125.2, 123.5,

115.4, 114.8, 112.1, 111.5, 104.2, 78.7, 43.5, 39.2, 38.9, 28.2. Calcd for C 18 ^H 22 ^N 2 O 3 Calculated: C% = 68.77, H% = 7.05, N% = 8.91; Found: C, 68.73; H, 7.15; N, 8.89.

C. 3- (N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) -5-nitro-1H-indole

5-Nitroindole was used, the reaction mixture was refluxed for 24 hours, and the residue was purified by chromatography on silica gel (200 g) eluting with a gradient of ethyl acetate / hexane (1: 2 to 1: 1) to give 72% yield. yielding the title compound as a yellow solid. Melting point: 230 ° C (dec.). ⁴ H-NMR (CDCl 3): δ 2.94 (bs, 1H), 8.78 (d, J = 1.3 Hz, 1H), 8.09 (dd, J = 1.4 and 9.4). H 2, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 6.17-6.15 (m, 1H), 4.16-4.13 (m, 2H),

3.68 (t,

J = 5.8 Hz, 2H), 2.58-2.48 (m, 2H), 1.50 (s, 9H);

Analysis calculated for C15 H21 N3 O4 · 0.1 H2O: C, 62.63; H, 6.19; N, 12.17; Found: C, 62.71; H, 6.09; N, 11.81.

Example 18

5-dibenzylamino-indole

To a mixture of 5-aminoindole (3.00 g, 22.7 mmol) and triethylamine (10.5 mL, 74.9 mmol, 3.3 equiv) in acetonitrile (30 mL) was added dropwise at room temperature under nitrogen atmosphere, 8.2 mL 68.9 mmol, 3.0 equivalents of benzyl bromide. The resulting reaction mixture was refluxed under nitrogen for 3 hours. The reaction mixture was filtered, the filtrate evaporated in vacuo and the residue chromatographed on a silica gel column (about 200 g) eluting with a gradient of ethyl acetate / hexane (1: 9 to 1: 1). The title compound is obtained in the form of an off-white solid. Mp 124.0-126.0 ° C; ¹³ C-NMR (acetone-dg) δ 144.3, 140.8, 131.8, 129.9, 129.2, 128.3, 127.5,

125.7, 113.5, 112.4, 106.4, 101.9, 57.0; TLC [15% ethyl acetate / hexane]: Rf = 0.3.

Example 19

5-nitroindole-3-N, N-dimethyl-glyoxamides

To a mixture of 5-nitroindole (10.00 g, 61.7 mmol) and phthalimide (4.00 g, 40% by weight) in anhydrous ether (250 mL) was added dropwise 17.0 mL (0.194 mol) of 3.1 equivalents of oxalyl chloride. The resulting mixture was stirred at room temperature under nitrogen for 72 hours. The resulting mixture was cooled to 0 ° C in an ice bath and gently stirred vigorously • · · ♦

A solution of 80 ml of ether and 80 ml of dimethylamine condensed at -78 ° C is added at 63 ° C. The resulting mixture was stirred vigorously at room temperature for 1 hour. The ether was evaporated in vacuo and the residue partitioned between water (500 mL) and methylene chloride (500 mL). The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid, the methylene chloride phase was removed and the aqueous phase was extracted with methylene chloride (3 x 500 mL). The methylene chloride extracts were combined, dried over magnesium sulfate and evaporated in vacuo. The residual solid was crystallized from methanol under reflux and then cooled. 5.74 g (22.0 mmol) of the title compound are obtained in the form of a pale yellow solid. Rf = 0.15 in methylene chloride containing 10% acetone. M.p. 248.0-249.0 ° C; IR (KBr) 1755, 1740, 1730, 1650, 1620, 1585, 1530 cm -1. ¹ H NMR (DMSO-d ₆ ) δ 12.9 (bs, NH), 8.97 (d, J = 2.3 Hz, 1H), 8.43 (s, 1H), 8.18 (dd, J = 2.3 and 9.0 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 3.02 (s, 3H), 2.95 (s, 3H) ; ¹³ C-NMR (DMSO-d ₆ ) δ 166.6, 143.2, 140.4,

140.2, 124.5, 118.9, 117.2, 114.2, 113.6, 36.8, 33.6; LRMS (m / Z, relative intensity): 261 (24, M +), 190 (29), 189 (100), 173 (15), 143 (83), 115 (23). HRMS calcd for C 12 H 11 ^N 3 ^O 4: 261.0750; found: 261.0746.

Analysis calculated for C 12 ^H 11 ^N 3 ^O 4: C, 55.17; H, 4.24; N, 16.08; Found: C, 5.15; H, 3.96; N, 15.96.

Example 20

3- (2-Dimethylamino-ethyl) -5-nitroindole

To a solution of 5-nitroindole-3-N, N-dimethylglyoxydamide (5.36 g, 20.52 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added dropwise with stirring 78.8 mL (78.8 mmol, 3.8 equiv.) , 0 mol / L borane in tetrahydrofuran. The resulting mixture was stirred at room temperature under nitrogen for 16 hours. Then, saturated aqueous sodium bicarbonate solution (200 mL) was carefully added and the resulting aqueous mixture was extracted with diethyl ether (3 x 150 mL). The ethereal extracts were combined, dried over magnesium sulfate and concentrated in vacuo. 6.9 g of 3- (2-dimethylaminoethyl) -5-nitroindolborane complex are thus obtained in the form of an amorphous orange solid. 1 H-NMR (DMSO-d 6): δ 11.7 (br m, NH), 8.58 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 2.3 and 9.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.49 (broad s, 1H), 3.23-3.17 (m, 2H), 3.02 -2.97 (m, 2H), 2.63 (s, 6H). This solid was taken up in 150 ml of absolute ethanol with 6.9 g of cesium fluoride and 6.9 g of sodium carbonate, and the resulting mixture was refluxed under a nitrogen atmosphere for 16 hours. The mixture was then filtered through Celite ^F and the filtrate was concentrated in vacuo. The residual oil was chromatographed on silica gel (about 450 g) eluting with 8: 2: 0.1 methylene chloride: methanol: ammonium hydroxide. This gave 2.58 g (11.06 mmol) of the title compound as a yellow solid (54%). M.p. 133.0-135.0 ° C; IR (KBr): 1625, 1575, 1550, 1520, 1480, 1470, 1460, 1445, 1380, 1370, 1330 cm -1; 1 H-NMR (DMSO-d 6): δ 11.55 (br m, NH), 8.48 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 2.3 and 9.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.40 (broad s, 1H), 2.88-2.83 (m, 2H), 2.53 -2.48 (m, 2H), 2.19 (s, 6H); ¹³ C NMR (DMSO-d 6): 140.2, 139.3, 126.6, 126.5, 116.3,

9 9 9 • · «

65 116.0, 115.6, 111.7, 59.8, 45.1, 22.7; LRMS (m / z, relative intensity): 233 (7, M +), 189 (7), 188 (8), 143 (10), 129 (23),

115 (14), 59 (36), 58 (100). HRMS calcd for C 12 H 15 N 3 O 2 233.1166; found: 233.1155.

Analysis ^H 15 Cl 2 ^N 3 O 2 wherein:

Found: C, 61.79; H, 6.48; N, 18.01;

Found: C, 61.39; H, 6.45; N, 17.68.

Example 21

5-Amino-3- (2-dimethylamino-ethyl) indole

A mixture of 3- (2-dimethylaminoethyl) -5-nitroindole (1.85 g, 7.93 mmol) and palladium on carbon (0.40 g, 20% by weight, 10%) in 30 ml of absolute ethanol was prepared 2.94 x shaken for 6 hours at 10 ⁵ Pa pressure in a hydrogen gas atmosphere. The resulting mixture was filtered through Celite ^R filter aid and the Celite pad was washed with copious amounts of absolute ethanol. The combined filtrates were evaporated in vacuo to give the title compound (1.60 g, 7.87 mL, 99%) as a clear, slightly dark hygroscopic oil. IR (CHCl ₃ ): 3480, 1610, 1585, 1460, 1335 cm -1; ¹ H-NMR (CDCl 3): δ 8.10 (broad m, NH), 7.12 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H). , 6.88 (d, J = 2.2 Hz, 1H), 6.64 (dd, J = 2.2 and 8.5 Hz, 1H), 2.89-2.84 (m, 2H), 2.64-2.58 (m, 2H), 2.34 (s,

6H); ¹³ C-NMR (CDCl 3) δ 139.1, 131.2, 128.3, 122.2, 113.1, 112.9,

111.7, 103.8, 60.3, 45.4, 23.7; LRMS (m / z, relative intensity):

203 (9, M +), 158 (2), 145 (6), 83 (66), 58 (100). HRMS calcd for C12H17N3 203.1424, found 203.1418.

Analysis: Calculated for C12H17N3 * 1/2 H2O: C, 67.89; H, 8.55; N, 19.79; Found: C, 67.71; H, 8.60; N, 19.41.

• · · · 9 · · · · * 4 • ♦ * ♦ ··· «• · · <« ········ · · · · «4 i ··

Example 22

General Procedure for the Preparation of N- (Indol-5-yl) -Ν-Benzoylthiourea Derivatives

Benzyl chloride (0.68 mL, 5.90 mmol, 1.2 equiv.) Was added portionwise to a stirred solution of ammonium thiocyanate (0.45 g, 5.90 mmol, 1.2 equiv.) In acetone (10 mL) and the resulting mixture was stirred under nitrogen for 1 hour. reflux. The reaction mixture was cooled and 5.00 mmol of the appropriate 5-aminoindole was added, and the resulting solution was refluxed under nitrogen for 3 hours. The resulting mixture was then concentrated in vacuo and the residue taken up in 10 mL of saturated aqueous sodium bicarbonate. This aqueous mixture was extracted with ethyl acetate (2 x 10 mL), the extracts were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was chromatographed on a silica gel column (75 g), eluting with a 9: 1: 0.1 mixture of methylene chloride, methanol and ammonium hydroxide. The title compound is obtained.

According to the above procedure, the following compounds were prepared:

A. N- [3- (N-Methyl-pyrrolidin-2-ylmethyl) -1H-indol-5-yl] -5'-benzoylthiourea (R) -5-Amino-3- (N-methyl) pyrrolidin-2-ylmethyl) -1H-indole is used. After chromatographic separation, 46% of the title compound is obtained as a yellow foam. ¹³ C-NMR (CDCl 3) < 5

178.8, 167.0, 135.0, 133.6, 131.7, 129.5, 129.1, 127.6, 127.5,

123.4, 119.2, 115.0, 114.3, 111.4, 66.6, 57.4, 40.8, 31.4, 29.8, 21.8; [a] ²⁵ = + 62 ° [c = 2, CDC1 _3].

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·’Ll’d: I’ -: - - • • • • •

Analysis calculated for C22 H24 N4 OS · 0.4 CH2 Cl2: C, 63.08; H, 5.86; N, 13.14. Found: C, 62.76; H, 5.94; N, 12.94.

B. N- [3- (2-Dimethylaminoethyl) -1H-indol-5-yl) -5'-benzoylthiourea (R) -5-Amino-3- (2-dimethylaminoethyl) ) -ΙΗ-indole is used. After chromatographic separation, the title compound was obtained as a yellow foam in 22% yield. Rf = 0.4 [9: 1: 0.1 methylene chloride / methanol / ammonium hydroxide]; HRMS calculated for C2oH22 ^{os N4} O: 366.1517; found: 366.1467.

Calcd for C 20 ^H 22 ^N 4 ^OS '2CH2CI2 O: Calculated: C% = 63.27, H% = 5.89, N% = 14.61; Found: C, 63.53; H, 5.83; N, 14.61.

Example 23

General procedure for the preparation of N- (Indol-5-yl) thiourea derivatives

To a solution of 5.5 mol N- (indol-5-yl) -N'-benzoylthiourea in 40 ml of absolute ethanol was added dropwise a solution of 3.00 g of sodium hydroxide in 28 ml of water. The resulting reaction mixture was refluxed for 1 hour. The ethanol was then evaporated in vacuo and the pH of the remaining aqueous mixture was adjusted to 10 using concentrated hydrochloric acid and solid sodium carbonate. This aqueous mixture was extracted with ethyl acetate (3 x 50 mL), the extracts were combined, dried over sodium sulfate and evaporated in vacuo. The residue is used as such or crystallized from methylene chloride. so the title ve- ··· »··» e ··• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Add · · · ··

- We win 68 congregations.

Using the above procedure, the following compounds were prepared.

A. N- [3- (N-Methyl-pyrrolidin-2-ylmethyl) -1H-indol-5-yl] -thiourea

The residue was directly obtained as a yellow solid in 73% yield. Rf = 0.15 in acetone containing 10% triethylamine. 1 H NMR (CD 3 OD) δ 7.29 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.11 (s, 1H), 6, 78 (dd, J = 8.6 and 2.2 Hz, 1H), 4.91 (s, 4H), 3.23-3.13 (m, 2H), 2.75-2.40 (m, 3H), 2.52 (s, 3H), 1.94-1.57 (m, 4H).

B. N- [3- (2-Dimethylaminoethyl) -1H-indol-5-yl] thiourea

Crystallization of the extraction residue from methylene chloride gave the title compound as a beige solid (28%). Melting point: 190.0-191.0 ° C;

¹³ C-NMR (acetone-dg) δ 183.6, 136.0, 128.9, 124.4, 120.2, 116.4, 115.0, 112.7, 61.1, 45.6, 24.1; HRMS calcd for [C ₁₃ H ₁₈ N ₄ S · Η] 263.1333, found 263.1291.

Example 24

General procedure for the preparation of 5- (4-Benzyl-1,3-thiaz-2-ylamino) -1H-indole derivatives

To a solution of 1.00 mmol N- (indol-5-yl) thiourea in 5 mL absolute ethanol was added 0.27 g (1.0 mmol) 1 equivalent of 1-phenyl-3-chloro-3-propanone and the the resulting solution was refluxed under a nitrogen atmosphere for 3 hours. To the resulting reaction mixture was added 10 ml of saturated aqueous sodium bicarbonate solution and the mixture was stirred at room temperature for 30 minutes. The ethanol was evaporated in vacuo and the resulting aqueous mixture was extracted with ethyl acetate (2 x 10 mL). The extracts were combined, dried over sodium sulfate and evaporated in vacuo. The residue was purified by crystallization or column chromatography on silica gel (25 g) eluting with methylene chloride / methanol / ammonium hydroxide (9: 1: 0.1) to give the title compound.

Using the above procedure, the following compounds were prepared.

A. 5- (4-Benzyl-1,3-thiaz-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole

Chromatography afforded the title compound as an off-white solid (3%). ¹³ CNMR (acetone-dg) δ 167.0, 153.1, 140.7, 134.4, 134.0, 129.7,

128.9, 126.7, 124.3, 124.0, 115.5, 113.9, 112.3, 109.4, 101.8,

67.3, 58.0, 41.0, 38.7, 30.5, 22.5; HRMS calculated for C ₂ 4 H 6 ^N ₂ O 4 ^S: 402.1881; found: 402.1872.

B. 5- (4-Benzyl-1,3-thiaz-2-ylamino) -3- (2-N, N-dimethylaminoethyl) -1H-indole

Trituration of the extraction residue afforded the title compound as an off-white solid (20%). Melting point: 170.5-172.0 ° C; ⁴³ C-NMR (acetone-dg) δ 167.2,

153.1, 140.7, 134.4, 134.1, 129.8, 128.9, 126.7, 123.9, 115.7,

114.3, 112.3, 109.4, 101.8, 61.1, 45.6, 38.7, 24.3; HRMS calcd for C22H24N4S 376.1724; found:

376.1685.

Analysis results for C22H24N4S · 0.4 H2O:

- 70%: C, 68.86; H, 6.51; N, 14.60. Found: C, 68.98; H, 6.18; N, 14.44.

Example 25

5-Amino-3 - [(2R, 4R) -N-methyl-4-pyrrolidin-2-ylmethyl] indole

5- (2,5-Dimethyl-1H-pyrrolyl) -3 - [(2R, 4R) -N-methyl-4-methoxypyrrolidin-2-ylmethyl] -2H (2.20 g, 6.52 mmol) -indole, 7.25 g, 104 mmol, 16 equivalents of hydroxylamine hydrochloride and 7.28 mL,

A mixture of 52.2 mmol (8 equivalents) of triethylamine in 22 ml of 2-propanol was heated at reflux for 8 hours under nitrogen. The reaction mixture was evaporated in vacuo and the residue partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The ethyl acetate layer was removed and the aqueous layer was extracted with methylene chloride (3 x 50 mL). All the organic extracts were combined and dried over magnesium sulfate, and the solution was concentrated in vacuo. This gave 1.68 g (100%) of the title compound as an off-white, amorphous solid. Rf = 0.4 (9: 1: 0.1 methylene chloride / methanol / ammonium hydroxide mixture]; ^4H-

NMR (CD ₃ OD): δ = 7.14 (d, J = 8.5 Hz, 1H), 6.99 (s, 1H), 6.94 (bs, 1H), 6.68 (bd) , J = 8.5 Hz, 1H), 4.90 (s, 3-NH), 3.86-3.77 (m, 1H), 3.24 (s, 3H), 3.24-3, 13 (m, 2H), 2.93-2.80 (m, 1H), 2.69 (dd, J = 13.7 and 9.7 Hz, 1H), 2.51 (s, 3H), 2.402 , 18 (m, 2H), 1.73-1.63 (m, 1H); ¹³ C-NMR (CD 3 OD) δ 139.7, 133.4,

129.3, 124.4, 114.4, 112.8, 111.2, 105.5, 79.3, 68.3, 66.1,

56.7, 40.7, 39.5, 30.1.

i

Example 26

5- (2,5-Dimethyl-1H-pyrrolyl) -3 - [(2R, 4R) -N-methyl-4-methoxy-pyrrolidin-2-ylmethyl] -1H-indole

3.24 g, 6.87 mmol 3 - [(2R, 4R) -N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl) -5- (2,5-dimethyl-1H-pyrrolyl) -1H of indole as a solid was added portionwise to a mixture of lithium aluminum hydride (1.65 g, 43.5 mmol, 6.3 equiv.) in dry tetrahydrofuran (80 mL), and the resulting mixture was refluxed under nitrogen for 24 hours. Water (1.65 mL), 2N sodium hydroxide solution (1.65 mL), water (5 mL), and ethyl acetate (30 mL) were carefully added successively. The resulting mixture was stirred at room temperature for 12 hours and then filtered. The filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column (about 60 g) and eluted with a 12: 1: 0.1 mixture of methylene chloride, methanol and ammonium hydroxide. This gave 2.20 g (95%) of the title compound as a white foam. R f = 0.5 (9: 1: 0.1 in methylene chloride / methanol / ammonium hydroxide): ¹ H NMR (CDCl ₃ ): δ 8.88 (bs, NH), 7.43 ( d, J = 1.8

H 2, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H),

6.98 (dd, J = 8.4 and 1.9 Hz, 1H), 5.94 (s, 2H), 3.80-3.74 (m,

1H), 3.30-3.21 (m, 2H), 3.28 (s, 3H), 2.73 (dd, J = 14.1 and 9.6

Hz, 1H), 2.56-2.43 (m, 1H), 2.45 (s, 3H), 2.30 (dd, J = 10.9 and 5.6, 1H), 2.25- 2.15 (m, 1H), 2.06 (s, 6H), 1.72-1.64 (m, 1H);

¹³ C-NMR (CDCl 3): δ 135.5, 130.7, 129.4, 128.5, 127.8, 127.0,

123.9, 122.1, 118.4, 113.7, 111.5, 105.0, 78.5, 66.0, 62.5,

56.4, 40.6, 39.2, 29.7, 13.2; FAB HRMS calculated: 338.2234, found 338.2247.

I

Example 27

3 - [(2R, 4R) -N-Benzyl-1-oxycarbonyl-pyrrolidine-2-yl-carbonyl] -5- (2,5-dimethyl-1H-pyrrolyl) -1H-indole

5.22 g (18.8 mmol) of (2R, 4R) -4-methoxy-proline (Krapcho et al., J. Med. Chem., 1148 (1988)) trace (0.5 ml) of N, N-dimethyl- To a solution of formamide in 50 ml of anhydrous methylene chloride is added dropwise with stirring, 2.44 ml, 28.0 mmol, 1.5 equivalents of oxalyl chloride. The resulting foaming solution was stirred at room temperature under nitrogen for 2 hours. The mixture was concentrated in vacuo, treated with hexane (2 x 20 mL), and the remaining proline acid chloride was dissolved in benzene (25 mL). At the same time, a solution of 7.22 g (38.0 mmol, 2.0 equiv.) Of 5- (2,5-dimethyl-1H-pyrrolyl) -1H-indole in 30 mL of benzene was added with stirring to 13.0 mL, 39 mmol, 0 equivalents of a 3.0 M solution of ethyl magnesium bromide and the resultant foaming solution were stirred under nitrogen at room temperature for 30 minutes and then cooled to 0 ° C. To this indole magnesium salt at 0 ° C is added rapidly, with vigorous stirring, a benzene solution of proline acid chloride. The resulting mixture was stirred under nitrogen atmosphere at 0 ° C for 10 minutes, then 80 mL of saturated aqueous sodium bicarbonate solution was added and the aqueous mixture was extracted with ethyl acetate (2 x 80 mL). The organic layers were combined, dried over magnesium sulfate and evaporated in vacuo. The residual oil was crystallized by stirring overnight in 80 ml of diethyl ether. This gave 7.15 g (81%) of the title compound as a white solid. Melting point: 189.0-191.0 ° C;

Rf = 0.4 (2: 1 ethyl acetate: hexane); FAB HRMS calcd for ^C 28 ^H 29 ^N 3 ^O 4 * ^H : 472.2238; found: 472.2281.

Example 28

5- (2,5-Dimethyl-lH-pyrrolyl) indole

A mixture of 1.32 g, 10.0 mmol of 5-aminoindole, 4.0 mL, 34 mmol, 3.4 equivalents of acetonylacetone and 25 mL of toluene was heated at reflux for 24 hours under nitrogen atmosphere using a Dean-Stark trap. . The mixture was cooled, poured onto a filter containing about 200 g of silica gel, and washed with 10% ether in hexane to give the title compound (1.52 g, 72%) as an off-white crystalline solid. Rf = 0.75 in diethyl ether; ¹³ C-NMR (CDCl 3) δ 135.0,

131.4, 129.5, 128.1, 125.6, 122.4, 120.3, 111.3, 105.0, 103.0,

13.2.

Analysis: Calculated for C14H14N2: C, 79.97; H, 6.71; N, 13.32; Found: C, 79.72; H, 6.75; N, 13.13.

Claims (28)

Claims 1. A compound of formula (I) wherein Z is a group of formula (I) or (2) R 1 is a group of formula (3), (4), (5) or (6); X is -O-,> NH or -S-; A, B, D, E and F are each independently carbon, nitrogen, oxygen or sulfur; R ₂ , R 3, R 4, R 5 and R 9 are each independently hydrogen, C 1-6 alkyl, aryl, (C 1-3 alkyl) aryl, halogen, cyano or nitro, -NR 7 R 8, - (CH 2) n OR 9 , -SR8, -SO2R9, -SO2NR7R3, -NR7SO2R8 / -NR7CO2R9, -NR7COR9, -CONR7R8 or -CO2R9; R 2 and R 3, R 3 and R 4, R 4 and R 5 or R 5 and R 8 together are a 5-7 membered alkyl ring, a six membered aryl ring, a 5-7 membered heteroalkyl ring containing nitrogen, oxygen or sulfur or a 5 or 6 membered, one or a heteroaryl ring containing two nitrogen, oxygen and / or sulfur heteroatoms; R 7 and R 8 each independently represent hydrogen, C 1 -C 6 alkyl, - (CH 2) q R 10 / (C 1 -C 3 alkyl) aryl, aryl, or R 7 and R 8 together may form a 4- to 6-membered ring; Rg is hydrogen, (C1-C6) -alkyl, (C1-C3-alkyl) -aryl, aryl, or - (CH2) _w Rh; _R10 and Rn are independently -OR 12 / ^{- <3 θ2} κ 12 / -CONHR12 or a hydroxyl or cyano group; I - ^75r12 is hydrogen, (C1-C6) -alkyl, aryl or (C1-C6-alkyl) -aryl; R13 is hydrogen, -OR14, or -NHCOR14; R 14 is C 1-6 alkyl or C 1-3 alkylaryl; n is 0 1 obsession 2; m is 1 2 obsession 3; q is 2, 3 obsession 4; w is 2, 3 obsession 4; and the aryl moieties of the above aryl groups and alkylaryl groups are independently phenyl or substituted phenyl, wherein the substituent is one to three C 1-4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro and C 1-4 alkoxy groups. may; and the dotted line represents an optional double bond; and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R 1 is a group of formula (1), (2) or (6b), wherein R 7, R 8 and R 13 are as defined in claim 1. A compound according to claim 2, wherein Z is a group of formula (Ia) or (2a) wherein A, D, E, R ₂ , R 3, R 4 and R 5 are as defined in claim 1, X is -NH -. A compound according to claim 3, wherein R 1 is a group of formula (6c) wherein R 7 and R 13 are as defined in claim 1. A compound according to claim 4, wherein R 13 is hydrogen. A compound according to claim 4, wherein Z is a group of formula (Ia) wherein A, D, E, R 2, R 3, R 4 and R 5 are as defined in claim 1 and X is -NH-. A compound according to claim 2, wherein R 1 is a group of Formula 6a, wherein R 7 and R 13 are as defined in claim 1. A compound according to claim 7, wherein R 13 is -O-R 14 and R 14 is -CH 3. A compound according to claim 7, wherein Z is a group of formula (Ia), wherein A, D, E, R 2, R 3, R 4 and R 5 are as defined in claim 1, X is -NH. A compound according to claim 3 wherein Z is a group of Formula 14 wherein R ₂ is -NO ₂ , -CN, -SO ₂ CH 3, -SO ₂ Ph, -CONH _2, and X is -NH-. A compound according to claim 10, wherein is a group of Formula (6c) wherein R 7 and R 13 are As claimed in claim 1. A compound according to claim 1, which is one of the following: 3- (2-dimethylamino-ethyl) -5- (3,5-dinitro-pyrid-2-ylamino) -1H-indole; 3- (2-dimethylamino-ethyl) -5- (3-nitro-pyridin-2-ylamino) -ΙΗ-indole; 3- (2-dimethylamino-ethyl) -5- (3-trifluoromethyl-pyridin-2-ylamino) -lH-indole; (R) -5- (3-nitro-pyridin-2-ylamino) -3- (pyrrolidin-2-ylmethyl) -1H77 indole; (R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (nitro-pyrid-2-ylamino) -1H-indole; (R, S) -3- (N-Methyl-pyrrolidin-3-yl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole; 5- (benzoxazine-2-ylamino) -3- (2-dimethylamino-ethyl) -lH-indole; (R) -3- (N-Cyclopropylmethyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole; (R) -5- (3-Nitropyrid-2-ylamino) -3- [N- (2-propynyl) pyrrolidin-2-ylmethyl] -1H-indole; (R) -5- (3-nitro-pyridin-2-ylamino) -3- (N- (2-propenyl) pyrrolidin-2-ylmethyl) -1H-indole; (R) -5- (3-nitro-pyridin-2-ylamino) -3- (N-propyl-pyrrolidin-2-ylmethyl) -lH-indole; (R) -3- (N-butyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyridin-2-ylamino) -lH-indole; (R) -3- (N-ethyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyridin-2-ylamino) -lH-indole; (R) -5- (3-nitro-pyridin-2-ylamino) -3- (N-pentyl-2-ylmethyl) -lH-indole; (R) -3- (N- (2-Methoxy-ethyl) -pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole; (R) -3- [N- (2-Cyanoethyl) pyrrolidin-2-ylmethyl] -5- (3-nitropyrid-2-ylamino) -1H-indole; (R) -3- [N- (2-Cyanomethyl) -pyrrolidin-2-ylmethyl] -5- (3-nitropyrid-2-ylamino) -1H-indole; 5- (4-Benzyl-1,3-thiaz-2-ylamino) -3- (2-dimethylaminoethyl) -1H-indole; • · · - 78 (R) -5- (3-Benzylthio-1,2,4-thiadiaz-5-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole; 3- (2-dimethylamino-ethyl) -5- (pyrimidin-2-ylamino) -lH-indole; 3- (2-dimethylamino-ethyl) -5- (3-methylsulfonyl-pyridin-2-ylamino-ΙΗ-indole; (R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (2-nitrophenylamino) -1H-indole; (R) -5- (6-methoxy-3-nitro-pyridin-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -lH-indole; (R) -5- (4-methyl-3-nitro-pyridin-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -lH-indole; (R) -3- (N-methylpyrrolidin-2-ylmethyl) -5- (3-nitro-5-phenyl-pyridin-2-ylamino) -lH-indole; (R) -5- (3-cyano-pyridin-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -lH-indole; (R) -5- (6-Isopropoxy-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole; (R) -5- (4-cyano-2-nitro-phenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -lH-indole; (R) -3- (N-methylpyrrolidin-2-ylmethyl) -5- (4-trifluoromethyl-2-nitro-phenylamino) -lH-indole; (R) -5- (5,6-Dichloro-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole; 5- (4-cyano-2-nitro-phenylamino) -3 - [(2R, 4R) -N-methyl-4-pyrrolidin-2-ylmethyl] -lH-indole; 5- (4-benzyl-l, 3-thiazol-2-ylamino) -3- (2-dimethylamino-ethyl) -1H-indole; (R) -5- (3-Benzylthio-1,2,4-thiadiaz-5-ylamino) -3- (N-methylpyrrole · · · · * · - 79 lidin-2-ylmethyl) -α-indole; and (R) -5- (5-chloro-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole. 13. A pharmaceutical composition for the treatment of hypertension, depression, anxiety, eating disorders, obesity, drug addiction, headaches, migraine, pain, chronic, seizure-related unilateral headaches and headaches associated with vascular disorders. A compound of claim 1 and a pharmaceutically acceptable carrier. 14. A pharmaceutical composition for the treatment of a deficiency in serotonergic neurotransmission, comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier for the treatment of such disorders. A compound of formula II wherein X is -NH-, -O- or -S-; R 4 is a group of formula (4) or (6c); R7 is hydrogen, (C1-C6) -alkyl, - (CH2) qR10, (C1-C3-alkyl) -aryl, and aryl; R 14 is -OH, -OR 42 / -CO 2 R 12 '-CONHR 12, or cyano; R 13 is hydrogen, -OR 44 or -NHCOR 3; R 14 is C 1-6 alkyl or (C 1-3 alkyl) aryl; q is 2, 3 or 4; R12 is hydrogen, (C1-C6) -alkyl, aryl or (C1-C6-alkyl) -aryl; and the aryl units of the above groups and the alkylaryl groups are independently phenyl or substituted phenyl, Wherein the substituted phenyl group may have from 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, halogen, hydroxy-substituted, cyano, carboxamido, nitro, and C 1-4 alkoxy, and pharmaceutically acceptable salts thereof. A compound according to claim 17, wherein is a group of formula (6c) wherein R 7 and R 13 are a As claimed in claim 15. 17. A process for the preparation of a compound of formula I wherein Z is a group of formula (I) or (2), R 1 is a group of formula (3), (4), (5) or (6); X is -O-,> NH or -S-; A, B, D, E and F are each independently carbon, nitrogen; oxygen or sulfur; R2, R3, ^R4 , R5 and R8 are each independently hydrogen, (C1-C6) -alkyl, aryl, (C1-C3-alkyl) -aryl, halogen, cyano or nitro, -NR7R8, - (CH2) _m ° ^R 9 / "SRg, -SO2R9, -SO2NR7R8, -NR7SO2R8 / -NR7CO2R9, -NR7COR9, -CONR7Rg or -CO2R9; R 2 and R 3, R 3 and R 4, R 4 and R 5 or R 5 and R 8 together are a 5-7 membered alkyl ring, a six membered aryl ring, a 5-7 membered heteroalkyl ring containing a nitrogen, oxygen or sulfur heteroatom, or a 5- or 6-membered a heteroaryl ring containing nitrogen, oxygen and / or sulfur heteroatoms; R7 and R8 are independently hydrogen, C 1-6 alkyl, - (CH 2) q ^{R 10} / (C 1-3 alkyl) aryl, aryl, or R 7 and R 3 may be taken together to form a 4-6 membered ring; Rg is hydrogen, (C1-C6) -alkyl, (C1-C3-alkyl) -aryl, aryl, or - (CH2) _w Rh; RPO and Rp is independently selected from -OR12, _-CO2 Ri2 '-CONHR12 group or an hydroxy or cyano; ^r12 is hydrogen, (C1-C6) -alkyl, aryl or (C1-C6-alkyl) -aryl; Rp3 is hydrogen, -OR14, or -NHCOR14; R34 is (C1-C6) alkyl or (C1-C3) alkylaryl; n is 0 1 obsession 2; m is 1 2 obsession 3; q is 2, 3 obsession 4; w is 2, 3 obsession 4; and the aryl moieties of the above aryl groups and alkylaryl groups are independently phenyl or substituted phenyl, wherein the substituent is one to three C 1-4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro and C 1-4 alkoxy groups. may; and the dotted line represents an optional double bond; characterized in that a) for the preparation of compounds wherein Z is a group of the formula I and A, B, D, E, F, R 2, R 3, R 4, R 5 and R 8 are as defined in the foregoing - a compound of the formula II wherein X and Rj are as defined in the preceding claims, with a compound of formula IIIA wherein LG is a suitable leaving group, A, B, D, E, F, R ₂ , R 3, R 4, R 5 and R 8 are given in a circle -; obsession b) for the preparation of compounds wherein Z is 2 and A, B, D, E, R ₂ , R 3, R 4 and R 5 are as defined above, a compound of formula II wherein X and R 1 is reacted with a compound of formula (IIIB) as hereinbefore defined, wherein LG is a leaving group and A, B, D, E, R ₂ , R 3, R 4 and R 5 are as defined in the present invention, or c) for the preparation of compounds wherein R 1 is a group of formula (6) and R 7 and R 13 are as defined in the foregoing, a compound of formula (15) wherein Ζ, X and R With an alkylating agent of formula (G) wherein G is Cl, Br, I, -OSO ₂ CH ₃ , -OSO ₂ Ph, -OSO ₂ PhCH 3 or -OSO ₂ CF 3, and R 7 is as defined herein; obsession d) for the preparation of compounds wherein R 1 is a group of formula (6) and R 7 is - (CH ₂ ) q R 10, q is 2 and R 1 - q and R 13 are as defined in general formula (15). Ζ compound wherein X and R13 are as defined above - is reacted with an alkylating agent of formula CH ₂ = CHR ₁₀ - in which R10 is as defined above -; and optionally converting the resulting compound of formula (I) into a pharmaceutically acceptable salt. A process according to claim 17 for the preparation of compounds having the formula (3), (4) or (6b) as substituents wherein R7, R8 and R13 are As claimed in claim 17, wherein the appropriately substituted reagents are used. A process for the preparation of a compound of formula (I) according to claim 18 wherein Z is a group of formula (I) or (2) wherein A, D, E, R ₂ , R 3, R 4 and R 5 are and X is -NH-, wherein the appropriately substituted reagents are used. A process for the preparation of a compound of formula (I) according to claim 19 wherein R 1 is a group of formula (6c) wherein R 7 and R 13 are as defined in claim 17, wherein the appropriately substituted reagents are used. 21. The process of claim 20 for the preparation of compounds of formula I wherein R13 is hydrogen, wherein the appropriately substituted reagents are used. A process for the preparation of a compound of formula I according to claim 20 wherein Z is a group of formula I wherein A, D, E, R ₂ , R 3, R 4 and R 5 are as defined in claim 17, and X is -NH-, wherein the appropriately substituted reagents are used. A process for the preparation of a compound of formula (I) according to claim 18 wherein R 1 is a group of the general formula (6a) wherein R 7 and R 13 are as defined in claim 17 wherein the appropriately substituted reagents are used. 24. The process of claim 23 for the preparation of compounds of formula I wherein R13 is -OR14 and R14 is methyl, wherein the appropriately substituted reagents are used. A process for the preparation of a compound of formula I according to claim 23 wherein Z is a group of formula Ia wherein A, D, E, R 2, R 3, R 4 and R 5 are as defined in claim 17, and X is -NH-. 26. A process according to claim 19 for the preparation of compounds of formula I wherein Z is a group of formula 14 wherein R2 is -NO2, -CN, -SO2CH3, -SC2Ph, -CONH2 and X is -NH-, characterized in that the appropriately substituted reagents are used. 27. A process for the preparation of a compound of formula I according to claim 26, wherein R 1 is a group of formula 6c, wherein R 7 and R 13 are as defined in claim 17, wherein the appropriately substituted reagents are used. 28. The method of claim 17 a 3- (2-dimethylamino-ethyl) -5- (3,5-dinitro-pyrid-2-ylamino) -1H-indole; 3- (2-dimethylamino-ethyl) -5- (3-nitro-pyridin-2-ylamino) -lH-indole; 3- (2-dimethylamino-ethyl) -5- (3-trifluoromethyl-pyridin-2-ylamino) -lH-indole; 9 (R) -5- (3-nitro-pyrid-2-ylamino) -3- (pyrrolidin-2-ylmethyl) -1H-indole; (R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (nitro-pyrid-2-ylamino) -1H-indole; (R, S) -3- (N-methylpyrrolidin-3-yl) -5- (3-nitro-pyridin-2-ylamino) -lH-indole; 5- (benzoxazine-2-ylamino) -3- (2-dimethylamino-ethyl) -lH-indole; (R) -3- (N-Cyclopropylmethyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole; (R) -5- (3-nitro-pyridin-2-ylamino) -3- [N- (2-propynyl) pyrrolidin-2-ylmethyl] -lH-indole; (R) -5- (3-nitro-pyridin-2-ylamino) -3- [N- (2-propenyl) pyrrolidin-2-ylmethyl] -lH-indole; (R) -5- (3-nitro-pyridin-2-ylamino) -3- (N-propyl-pyrrolidin-2-ylmethyl) -lH-indole; (R) -3- (N-Butyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole; (R) -3- (N-Ethyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-pyrid-2-ylamino) -1H-indole; (R) -5- (3-Nitropyrid-2-ylamino) -3- (N-pentylpyrrolidin-2-ylmethyl) -1H-indole; (R) -3- (N- (2-methoxyethyl) pyrrolidin-2-ylmethyl) -5- (3-nitropyrid-2-ylamino) -lH-indole; (R) -3- [N- (2-Cyanoethyl) pyrrolidin-2-ylmethyl] -5- (3-nitropyrid-2-ylamino) -1H-indole; (R) -3- [N- (2-Cyanomethyl) pyrrolidin-2-ylmethyl] -5- (3-nitropyrid-2-ylamino) -1H-indole; 5- (4-Benzyl-1,3-thiaz-2-ylamino) -3- (2-dimethylaminoethyl) -NH · ··· · ··· - 86-indole; (R) -5- (3-Benzylthio-1,2,4-thiadiaz-5-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole; 3- (2-Dimethylaminoethyl) -5- (pyrimidin-2-ylamino) -1H-indole; 3- (2-Dimethylaminoethyl) -5- (3-methylsulfonylpyrid-2-ylamino-1H-indole; (R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (2-nitrophenylamino) -1H-indole; (R) -5- (6-Methoxy-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole; (R) -5- (4-Methyl-3-nitropyrid-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole; (R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (3-nitro-5-phenyl-pyrid-2-ylamino) -1H-indole; (R) -5- (3-Cyanopyrid-2-ylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole; (R) -5- (6-Isopropoxy-3-nitro-pyrid-2-ylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole; (R) -5- (4-Cyano-2-nitro-phenylamino) -3- (N-methyl-pyrrolidin-2-ylmethyl) -1H-indole; (R) -3- (N-Methyl-pyrrolidin-2-ylmethyl) -5- (4-trifluoromethyl-2-nitrophenylamino) -1H-indole; (R) -5- (5,6-Dichloro-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole; 5- (4-Cyano-2-nitrophenylamino) -3 - [(2R, 4R) -N-methyl-4-methoxypyrrolidin-2-ylmethyl] -1H-indole; 5- (4-Benzyl-1,3-thiaz-2-ylamino) -3- (2-dimethylaminoethyl) -1H-indole; · · · · · · · · · · · ·································· ((R ) -5- (3-Benzylthio-1,2,4-thiadiaz-5-ylamino) -3- (N-methylpyrroliodin-2-ylmethyl) -5-indole; and (R) -5- (5-chloro-2-nitrophenylamino) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole, characterized in that the appropriately substituted reagents used.